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2005.03.03. Dr. Pogány - WHO, Shanghai 1/58
Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines
János Pogány, pharmacist, PhD, consultant to WHO
Shanghai, 01 March 2005E-mail: [email protected]
QUALIFICATION and VALIDATION I.
2005.03.03. Dr. Pogány - WHO, Shanghai 2/58
Subjects for Discussion
1. Regulatory background, definitions
2. Characteristics of processes
3. Validation master plan (VMP)
4. Pharmaceutical manufacturing process validation (tablet-making)
5. Concluding remarks
2005.03.03. Dr. Pogány - WHO, Shanghai 3/58
WHO GMP and Guidelines Guideline on Submission of Documentation for
Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.
WHO good manufacturing practices (GMP): main principles for pharmaceutical products – Section 4. Validation of manufacturing processes.
Supplementary guidelines on good manufacturing practices (GMP): Validation (2003) – Draft.
2005.03.03. Dr. Pogány - WHO, Shanghai 4/58
Qualification QUALIFICATION is the „Action of proving that any
premises, (pharmaceutical utility) systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of „qualification”.
REQUALIFICATION is the main part of the preventive maintenance programme of proving that any premises, (pharmaceutical utility) systems and items of equipment work correctly and keep on leading to the expected results. (normal wear and tear)
2005.03.03. Dr. Pogány - WHO, Shanghai 5/58
Validation VALIDATION is the „Action of proving, in
accordance with the principles of GMP, that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to the expected results (see also qualification)”.
REVALIDATION is a part of the change control system of proving that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually keeps on leading to the expected results.
2005.03.03. Dr. Pogány - WHO, Shanghai 6/58
Qualification - Validation
Regulatoryrequirements
DQ,IQ,OQ inputs
DQ,IQ,OQ process
DQ,IQ,OQ outputs Process
Qualification Verification
Validation
Premises, equipment and supporting utilities must be qualified to operate in a validated process.
2005.03.03. Dr. Pogány - WHO, Shanghai 7/58
Technical pharmacy Pharmaceutical production system
(from purchasing API to packaging FP) Utility support system (HVAC, water, HPLC, etc.
equipment containing many items) Process (tablet making) (Unit) operation (granulation, compression) Step (sifting, sizing) Procedure, method, technique (SOP)
2005.03.03. Dr. Pogány - WHO, Shanghai 8/58
4.10 Scientific approach „Processes and procedures should be established on the basis
of the results of the validation performed.”
Objectives To prove that the tests, measurements, results and
interpretation of formal studies on (manufacturing) processes and procedures/methods are appropriate and accurate.
To stabilize new processes (to reduce variability, to increase batch to batch consistency of quality attributes of products).
To reduce defect levels (standardize yields). To reduce production costs.
2005.03.03. Dr. Pogány - WHO, Shanghai 9/58
Measure of variation (spread of data)
95.46%68.26%
2005.03.03. Dr. Pogány - WHO, Shanghai 10/58
Mean (average) chart
Normal variation
due to common causes
UCL Upper control limit
LCL Lower control limit
Abnormal variation of process – special causes
Abnormal variation of process – special causes
average = mean
2005.03.03. Dr. Pogány - WHO, Shanghai 11/58
Causes of variation Man (different operators - lack of proper training)
Machine / equipment (variation of tablet weight)
Measurement (lack of calibration)
Method (accuracy of validated analytical methods)
Material (batch-to-batch variation of the same crystal
form – different crystal forms (ASA)]
Environment (OoS T and RH in capsule filling)
2005.03.03. Dr. Pogány - WHO, Shanghai 12/58
Process under control Most points fall near the central line (68% within
one σ) A few points fall near the control limits (5% in
the third σ) Points shold balance on both sides of the mean Points should cross the mean line often. Points should show a random pattern (no trends,
cycles, clustering)
2005.03.03. Dr. Pogány - WHO, Shanghai 13/58
2005.03.03. Dr. Pogány - WHO, Shanghai 14/58
2005.03.03. Dr. Pogány - WHO, Shanghai 15/58
UNDER CONTROL
OUT OF CONTROL
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2005.03.03. Dr. Pogány - WHO, Shanghai 17/58
2005.03.03. Dr. Pogány - WHO, Shanghai 18/58
Innovator FPPs
Well-established, multisource, generic FPPs
2005.03.03. Dr. Pogány - WHO, Shanghai 19/58
GMP, QUALIFICATION and
VALIDATION STARTS WITH
DESIGN + CONSTRUCTION
OF FACILITIES AND
PURCHASING EQUIPMENT
2005.03.03. Dr. Pogány - WHO, Shanghai 20/58
Qualification Stage Validation Stage
Key elements Design Installation Operation Prospective Concurrent
Premises and Engineering phase Manufacturing Start-Up
Equipment
VMP Validation Protocols Validation Reports
Product and Process Developmental Phase Scale-Up Phase Manufacturing Phase
Validation of Critical variables Process Process & cleaning
analytical and Process optimization validation
methods selection Revalidation
Quality Development
VALIDATION MASTER PLAN (VMP)
ILLUSTRATIVE ISSUES
2005.03.03. Dr. Pogány - WHO, Shanghai 22/58
4.1-4.2 Validation master plan
1. „In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.
2. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan (VMP).”
2005.03.03. Dr. Pogány - WHO, Shanghai 23/58
Project oriented VMP Construction of new premises
Major renovation or additions to existing premises
First time validation of previously unvalidated processes (ARV FPPs)
Automation or computerized implementations that span a number of applications
2005.03.03. Dr. Pogány - WHO, Shanghai 24/58
Validation master plan The VMP is a summary document and should
therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents (Quality Manual), SOP's and Validation Protocols/Reports.
2005.03.03. Dr. Pogány - WHO, Shanghai 25/58
Content of VMP Approval (top management and all participating
departmental heads) Scope [separate VMPs for manufacturing processes,
pharmaceutical utility systems (e.g. HVAC, water)]. Responsibilities Production and QC premises (including controlled
environments)
Process and QC equipment
Pharmaceutical air (HVAC) and water systems
2005.03.03. Dr. Pogány - WHO, Shanghai 26/58
Content of VMP All critical utilities (such as compressed air, steam and
cooling liquids)
Computer control systems
Manufacturing processes
Product specifications including prospective IPC acceptance criteria
QC and IPC methods
2005.03.03. Dr. Pogány - WHO, Shanghai 27/58
Content of VMP Equipment cleaning
Validation requirements
Worker and environment safety
Change Control/Revalidation
Training requirements
Documentation requirements
Security plans
DESIGN,INSTALLATION and
OPERATION
QUALIFICATION
2005.03.03. Dr. Pogány - WHO, Shanghai 29/58
4.3 Documentary evidence
(a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ);
(b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ);
2005.03.03. Dr. Pogány - WHO, Shanghai 30/58
DQ and IQ DQ protocols and reports
GMP VMP National law Engineering design and construction documents
Do not start IQ before DQ has been completed! IQ/OQ protocols and reports
Above inputs + machine manuals Separate VMPs for HVAC and water systems
Do not start OQ before IQ has been completed!
2005.03.03. Dr. Pogány - WHO, Shanghai 31/58
4.3 Documentary evidence
(c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ);
(d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ).
2005.03.03. Dr. Pogány - WHO, Shanghai 32/58
Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines
Tablets
MANUFACTURING PROCESS VALIDATION
2005.03.03. Dr. Pogány - WHO, Shanghai 33/58
Risks in manufacturing processes Small quantity of waste creates serious danger to
health (1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972)
Low chance that patient or doctor recognizes non-conformance to specification in time (DEG in glycerol, 1996 - Haiti)
Limitations of sampling Percent of nonconformance:
0,1 1,0 5,0 10,0 Percent probability of release:
98 82 36 12
2005.03.03. Dr. Pogány - WHO, Shanghai 34/58
SAMPLING PROBLEM
The whole batch is released to the patient
But only the sample is tested
BATCH
Sample
2005.03.03. Dr. Pogány - WHO, Shanghai 35/58
Types of process validation
EXPERIMENTAL APPROACHPROSPECTIVE VALIDATION (R&D)
CONCURRENT VALIDATION (FIRST ≥3 BATCHES)
ANALYSIS OF HISTORICAL DATARETROSPECTIVE VALIDATION
(DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL APPROACH)
2005.03.03. Dr. Pogány - WHO, Shanghai 36/58
4.4 What should be validated?
„Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.”
2005.03.03. Dr. Pogány - WHO, Shanghai 37/58
4.8-4.9 Protocols and reports Validation studies are an essential part of GMP
and should be conducted in accordance with predefined and approved protocols.
A written report summarizing the results recorded and the conclusions reached should be prepared and stored.
2005.03.03. Dr. Pogány - WHO, Shanghai 38/58
Essential parts of the process validation protocol
Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation.
Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate).
Sampling plan — where, when, how and how many samples are taken.
Details of methods for recording and evaluation of results.
2005.03.03. Dr. Pogány - WHO, Shanghai 39/58
Illustrative variables of wet granulationProcess step Control or manipulate
(independent) variablesMeasured responses or output (dependent) variables
CrystallizationMicronization
Particle sizeBulk density
Dissolution timeGranulation and granule variables
Pre-mixing Speed, time, order of addition
Blend uniformity
Wet kneading Batch (load) sizeSpeed Impeller Chopper Spraying rateVolume of binder solutionGranulation time
End-point amperage Impeller Chopper Additional solvent volume
2005.03.03. Dr. Pogány - WHO, Shanghai 40/58
Illustrative variables of wet granulationProcess step Control or manipulate
(independent) variablesMeasured responses or output (dependent) variables
Drying Inlet air temperature (seasonal variation)Drying time (seasonal variation)Cooling time (if applicable)
Outlet air temperatureLODMoisture content
Sizing Screen type and size
Feed rate
Granule size distribution (variation of sub-batches)
Blending Batch size (sub-batches)SpeedBlending time
Blend uniformityBulk density untapped tappedFlowabilityYield
2005.03.03. Dr. Pogány - WHO, Shanghai 41/58
Illustrative variables of compression and film-coating
Process step Control or manipulate (independent) variables
Measured responses or output (dependent) variables
Compression
Machine speedGranule feed ratePrecompression forceCompression forcePunches and dies
Weight variationContent uniformityFriabilityHardnessThicknessDisintegrationDissolution time and profileYield
Film-coating Inlet air temperature (season)
Inlet air flow
Spray rate
Spray atomizing pressure
Outlet air temperature
Tablet-bed temperature
Coat quality
Yield
2005.03.03. Dr. Pogány - WHO, Shanghai 42/58
Illustrative variables of tablet packagingProcess step Control or manipulate
(independent) variablesMeasured responses or output (dependent) variables
Blistering Machine speedMachinability of blister materialForming temperatureForming pressureSealing temperatureSealing pressure
Leak testingAppearanceMinimum information is legibleYield
Bulk packing
Tablet counter
Incomplete tablets
Machine speed
Number of tablets
Detection, counting
Pilfer-proof
Labeling
Yield
2005.03.03. Dr. Pogány - WHO, Shanghai 43/58
Validation batches Process validation reports should be submitted in the
application for prequalification. Formal studies of production scale batches (not less
than three) are required to identify the critical variables.
Provisional equipment control parameters and the corresponding in-process acceptance criteria must be deduced from the results of experiments with the validation batches.
Critical parameters are to be monitored, non-critical ones should be tested occasionally.
2005.03.03. Dr. Pogány - WHO, Shanghai 44/58
4.5-4.7 Validation policy5. Qualification and validation should not be considered
as one-off exercises. An on-going programme should follow their first implementation and should be based on an annual review.
6. The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan.
7. The responsibility of performing validation should be clearly defined.
2005.03.03. Dr. Pogány - WHO, Shanghai 45/58
Process approachCONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM
CUSTOMER
REQUIREMENTS
CUSTOMER
SATISFACTION
Management responsibility
Resourcemanagement
Monitoring,improvement
Manufacture ProductInputs
2005.03.03. Dr. Pogány - WHO, Shanghai 46/58
Annual FPP quality review (1) Starting materials used in the product, especially those
from new sources. Critical in-process controls and finished product results. All batches that failed to meet established specification(s). All critical deviations or non-conformances and related
investigations. All changes carried out to the processes or analytical
methods. Marketing Authorisation variations submitted, or granted,
or refused, including those for third country dossiers.
2005.03.03. Dr. Pogány - WHO, Shanghai 47/58
Annual FPP quality review (2) Results of the stability monitoring programme. All quality-related returns, complaints and recalls,
including export only medicinal products. Adequacy of previous corrective actions. For new marketing authorisations, a review of post-
marketing commitments. A list of validated procedures and their revalidation
dates. A list of qualified equipment, support utility systems
and their requalification dates, including calibration programs.
2005.03.03. Dr. Pogány - WHO, Shanghai 48/58
Case summary of 20 batches (1)Statistics Av. wt. mg Dissolution % Assay %
Mean 347,6 99,6 98,2
Median 346,9 100,0 97,5
SD 5,2 2.5 2.2
Range 22.3 10.0 8.8
Minimum 337.0 95.6 95.0
Maximum 359.3 105.6 103.8
Conf. level, 95% 2.4 1.3 1.0
Accept. Crit. 350±5% 75%, 40' 90-110
2005.03.03. Dr. Pogány - WHO, Shanghai 49/58
Case summary of 20 batches (2)
1. Acceptance criteria for assay and dissolution
rate are loose and should be tightened.
2. Potential degradation products were not tested.
3. IPC data were not included in the retrospective
analysis of batch records.
4. Failures were not reported, etc.
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4.11 Analytical methods, computers and cleaning procedures
It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures.
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AUTOMATED SYSTEMS Protection of records, backups Access controls (use, read, write, execute,
delete, or create) Authentication (user ID and static passwords;
user ID and dynamic passwords; and biometric devices)
Audit-trail controls, and many other issues.
2005.03.03. Dr. Pogány - WHO, Shanghai 52/58
Current WHO GMP
Pro
cess
per
form
ance
Time
1992 version of WHO GMP
Without/before GMPPar
amet
ric re
lease
Problems
Stages of process validation
2005.03.03. Dr. Pogány - WHO, Shanghai 53/58
BEST PROCESS
MINIMUM REQUIRED INPUT
MAXIMUM OUTPUT
AT NO COST TO SOCIETY (industrial safety, labour safety, internal and external environment protection)
2005.03.03. Dr. Pogány - WHO, Shanghai 54/58
Costs of qualityVisible costs, e.g., waste and returned goods
Hidden costs, e.g., wrong decisions, non-competitive manufacturing process,low yield, maintenance, idle machine time, workers attitude, etc.
2005.03.03. Dr. Pogány - WHO, Shanghai 55/58
Main points again High quality FPPs can be manufactured only with
high quality processes under control. Premises, equipment and supporting utilities must
be qualified to operate in validated processes. Testing QC samples of FPPs does not guarantee
the quality of the whole batch, or the batch-to-batch consistency of quality.
Validation activities must be organized (VMP) and documented (protocols, records, reports, etc.)
2005.03.03. Dr. Pogány - WHO, Shanghai 56/58
Main points again Prospective and concurrent validations help to
understand what is critical for quality and shows the level of quality, which can be achieved with the available resources.
Qualification and validation should not be considered as one-off exercises.
Quality of FPPs should be reviewed annually. The best process is the most efficient both from
technical and economic/financial points of view.
2005.03.03. Dr. Pogány - WHO, Shanghai 57/58
Literature Pharmaceutical Process Validation, edited by: R. A.
Nash; Alfred H. Wachter, An International Third Edition, Revised and Expanded, Marcel Dekker, Inc. New York, Basel, Hong Kong (2003).
Marjo-Riitta Helle et al.: A literature review of pharmaceutical process validation, 52 references, Pharmaceutical Technology Europe, August 2003.
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THANK YOU
谢谢 !