Training on basic aspect of Good

Manufacturing Practices (GMP)

Section 4.
QUALIFICATION and
VALIDATION
János Pogány, Ph.D., consultant to WHO
Bangkok, 20 October 2004
E-mail: pogany@axelero.hu

2004.10.20 Dr. Pogány - WHO, Bangkok 1/49

 SUPPORTING GUIDELINES
 WHO good manufacturing practices: main
principles for pharmaceutical products
-Validation of manufacturing processes

 Supplementary guidelines on good

manufacturing practices (GMP): Validation
(2003) - Draft

2004.10.20 Dr. Pogány - WHO, Bangkok 2/49

 TECHNICAL PHARMACY
 PHARMACEUTICAL PRODUCTION
SYSTEM (PURCHASING > PACKAGING)
 UTILITY SUPPORT SYSTEM
 PROCESS (TABLET MAKING)
 (UNIT) OPERATION (GRANULATION)
 STEP (SIFTING, SIZING)
 PROCEDURE, METHOD (SOP)

2004.10.20 Dr. Pogány - WHO, Bangkok 3/49

 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, system and equipment ... keeps
on leading to the expected results.
2004.10.20 Dr. Pogány - WHO, Bangkok 4/49
 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 ... keeps on leading to...
(normal wear and tear)

2004.10.20 Dr. Pogány - WHO, Bangkok 5/49

QUALIFICATION - VALIDATION
 Premises, equipment and supporting utilities
must be qualified to operate in a validated
process. (E.g. you qualify an autoclave
(analytical instrument), whereas you validate
a sterilization (assay, impurity test) process
(method, operation).

2004.10.20 Dr. Pogány - WHO, Bangkok 6/49

 4.1-4.2 VALIDATION MASTER PLAN
 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.
 The key elements of a qualification and
validation programme of a company should
be clearly defined and documented in a
validation master plan (VMP).

2004.10.20 Dr. Pogány - WHO, Bangkok 7/49

VALIDATION MASTER PLAN
 Cover manufacturer’s validation policy and
needs
 Provides information on validation organization
 It should describe:
– why? - by whom?
– what? - how?
– where? - when?

2004.10.20 Dr. Pogány - WHO, Bangkok 8/49

 VALIDATION MASTER PLAN (1)
 PRODUCTION AND QC PREMISES, IN-CLUDING
CONTROLLED ENVIRONMENTS
 PROCESS AND QC EQUIPMENT
 PHARMACEUTICAL AIR (HVAC) AND WATER
SYSTEMS
 ALL CRITICAL UTILITIES, e.g., COMPRESSED
AIR, STEAM, COOLING LIQUIDS
 COMPUTER CONTROL SYSTEMS

2004.10.20 Dr. Pogány - WHO, Bangkok 9/49

 VALIDATION MASTER PLAN (2)
 QC AND IPC METHODS
 MANUFACTURING PROCESS
 EQUIPMENT CLEANING
 PRODUCT QUALITY
 REVALIDATION PROGRAM
 WORKER AND ENVIRONMENT SAFETY
 COMPUTER CONTROL SYSTEMS
2004.10.20 Dr. Pogány - WHO, Bangkok 10/49
 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); VMP
(b) the premises, supporting utilities and equipment have been
built and installed in compliance with their design
specifications (installation qualification or IQ); manual + law
(c) the premises, supporting utilities and equipment operate in
accordance with their design specifications (operational
qualification or OQ); manual
(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).

2004.10.20 Dr. Pogány - WHO, Bangkok 11/49

VALIDATION DOCUMENTS/1
QUALIFICATION PROTOCOLS:
 ENGINEERING DESIGN AND
CONSTRUCTION DOCUMENTS
 MACHINE MANUALS
– INSTALLATION QUALIFICATION (IQ)
– OPERATION QUALIFICATION (OQ)

2004.10.20 Dr. Pogány - WHO, Bangkok 12/49

 VALIDATION DOCUMENTS/2
VALIDATION PROTOCOLS:

 OPERATION QUALIFICATION REPORT FOR

PERFORMANCE QUALIFICATION (PQ)

 DEVELOPMENT PHARMACEUTICS DOCUMENTS

 PRODUCT FILES AS WELL AS BATCH

MANUFACTURING, QC AND IPC RECORDS

2004.10.20 Dr. Pogány - WHO, Bangkok 13/49

 VALIDATION DOCUMENTS/3
MAIN OUTPUTS INCLUDE:
 QUALIFICATION REPORTS
 VALIDATION REPORTS
 SOPs INCLUDING EQUIPMENT CLEANING
 REQUALIFICATION AND REVALIDATION
PROGRAM
 PREVENTATIVE MAINTENANCE PROGRAM

2004.10.20 Dr. Pogány - WHO, Bangkok 14/49

GMP, QUALIFICATION and
VALIDATION STARTS WITH
DESIGN + CONSTRUCTION
OF FACILITIES AND
PURCHASING EQUIPMENT
2004.10.20 Dr. Pogány - WHO, Bangkok 15/49
 Qualification Stage Validation Stage
Key elements Design & C Installation Operation Prospective Concurrent

Facilities and Engineering phase Manufacturing Start-Up

Equipment

VMP (Validation Protocols) (Batch Records and Validation documentation)

Product and Process Developmental Phase Scale-Up Phase Manufacturing

Phase
(Validation of (Critical variables (process optimization (Biobatch,
analytical and Stability Testing) and pilot production) reproducible
methods) quality)

Quality Development

2004.10.20 Dr. Pogány - WHO, Bangkok 16/49

 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.

2004.10.20 Dr. Pogány - WHO, Bangkok 17/49

 TYPES OF VALIDATION
EXPERIMENTAL APPROACH
PROSPECTIVE VALIDATION (R&D)
CONCURRENT VALIDATION (FIRST ≥3 BATCHES)

ANALYSIS OF HISTORICAL DATA

RETROSPECTIVE VALIDATION
(DIFFERS CONCEPTUALLY FROM THE
EXPERIMENTAL APPROACH)

2004.10.20 Dr. Pogány - WHO, Bangkok 18/49

CONCURRENT VALIDATION
1. FIRST THREE PRODUCTION SCALE BATCHES ARE
MONITORED EXTENSIVELY
2. PROVISIONAL IPC ACCEPTANCE CRITERIA ARE
ESTABLISHED
3. MACHINERY AND EQUIPMENT PARAMETERS ARE
DESCRIBED IN SOPs
4. CRITICAL ASPECTS ARE MONITORED, NON-
CRITICAL ONES ARE TESTED OCCASIONALLY
5. CONCURRENT VALIDATION NEVER ENDS

2004.10.20 Dr. Pogány - WHO, Bangkok 19/49

 IN-PROCESS CONTROL
PROCESS PARAMETERS AND THE
CORRESPONDING IN-PROCESS
CONTROLS MUST BE DEDUCED FROM
THE KNOWLEDGE ACTUALLY
AVAILABLE AT THE TIME, BASED ON
EXPERIENCE FROM DEVELOPMENT
PHARMACEUTICS AND HISTORICAL
EXPERIENCE WITH DOSAGE FORM

2004.10.20 Dr. Pogány - WHO, Bangkok 20/49

 CONTINUOUS IMPROVEMENT
1. ALL POTENTIALLY CRITICAL
PARAMETERS SHOULD BE MONITORED.
2. FEEDBACK LOOP WOULD CORRELATE
THE QC AND IPC DATA WITH THE
QUALITY OF THE FINISHED PRODUCT.
3. AFTER CORRELATION ANALYSIS HAS
BEEN FINALIZED, IPC ACCEPTANCE
CRITERIA ESTABLISHED, ONLY
CRITICAL PARAMETERS ARE TO BE
MONITORED

2004.10.20 Dr. Pogány - WHO, Bangkok 21/49

 EXAMPLES OF CRITICAL QUALITY PARAMETERS

 Critical API parameters: purchasing specifications

 Critical operation parameters: chopper and impeller
speeds, drying temperature, LOD, porosity, etc. of
the granules may affect the quality and stability of
tablets. Internal customer.
 Critical equipment parameters: homogenization of
granules, RPM of the tableting machine.
 Critical product parameters: hardness, friability and
thickness of tablets may affect the packing
operation.
2004.10.20 Dr. Pogány - WHO, Bangkok 22/49
TABLET MANUFACTURING VARIABLES (1)
OUTPUT VARIABLES (validated quality,
yields) MANIPULATE (independent)
VARIABLES
 Binder
 Solvent
 dryer inlet temperature
 blending parameters
 RPM of the tabletting machine

2004.10.20 Dr. Pogány - WHO, Bangkok 23/49

TABLET MANUFACTURING VARIABLES (2)
 STATE (dependent) VARIABLES (IPC)
 granulation yield
 LOD of the compression blend
 flowing properties of the compression
blend
 tablet hardness, friability, weight
 tablet compression yield
 coated tablet yield, and so on

2004.10.20 Dr. Pogány - WHO, Bangkok 24/49

 4.5-4.7 VALIDATION POLICY
 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.
 The commitment to maintain continued validation
status should be stated in the relevant company
documentation, such as the quality manual or
validation master plan.
 The responsibility of performing validation should
be clearly defined.

2004.10.20 Dr. Pogány - WHO, Bangkok 25/49

 PROCESS APPROACH
CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM

C S
A C
Management
U responsibility
T
I U
S R
S
F S
E
T Q
A
C T
U Resource Monitoring,
O I management improvement
T
I O
R
M E
O
N M
M
E E
Inputs E
R N Manufacture Product
T
S
R

2004.10.20 Dr. Pogány - WHO, Bangkok 26/49

 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.

2004.10.20 Dr. Pogány - WHO, Bangkok 27/49

 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 programmes.
2004.10.20 Dr. Pogány - WHO, Bangkok 28/49
 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

2004.10.20 Dr. Pogány - WHO, Bangkok 29/49

CASE SUMMARY of 20 BATCHES (2)

1. ACCEPTANCE CRITERIA FOR ASSAY

AND DISSOLUTION RATE ARE LOOSE
2. POTENTIALLY CRITICAL IMPURITIES
ARE NOT TESTED
3. IPC DATA ARE NOT INCLUDED IN THE
RETROSPECTIVE ANALYSIS OF BATCH
RECORDS

2004.10.20 Dr. Pogány - WHO, Bangkok 30/49

 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.

2004.10.20 Dr. Pogány - WHO, Bangkok 31/49

 4.10 SCIENTIFIC APPROACH
 Processes and procedures should be
established on the basis of the results of the
validation performed.

2004.10.20 Dr. Pogány - WHO, Bangkok 32/49

4.11 QC, COMPUTERS and CLEANING
 It is of critical importance that particular
attention is paid to the validation of
analytical test methods, automated systems
and cleaning procedures.

2004.10.20 Dr. Pogány - WHO, Bangkok 33/49

 ANALYTICAL METHODS
 Qualified and calibrated instruments
 Documented methods
 Reliable reference standards
 Qualified analysts
 Sample integrity

2004.10.20 Dr. Pogány - WHO, Bangkok 34/49

CRITERIA FOR DIFFERENT METHODS
 selectivity
 precision
 repeatability
 intermediate precision
 reproducibility
 accuracy
 linearity
 range
 limit of detection
 limit of quantitation
 robustness, ruggedness

2004.10.20 Dr. Pogány - WHO, Bangkok 35/49

 ACCURACY AND PRECISION

InaccurateInaccurate
and &
imprecise
imprecise

Accurate but
imprecise
Inaccurate but
Precise Accurate Accurate and precise
precise

2004.10.20 Dr. Pogány - WHO, Bangkok 36/49

 CLASSES OF ANALYTICAL TESTS
 Class A: To establish identity
 Class B: To detect and quantitate impurities
 Class C: To determine quantitatively the
concentration
 Class D: To assess the characteristics

2004.10.20 Dr. Pogány - WHO, Bangkok 37/49

CRITERIA FOR ANALYTICAL CLASSES

Criteria A Bq Bd C D
Accuracy X X X
Precision X X X
Robustness X X X X X
Linearity and range X X X
Specificity X X X X X
Limit of detection X
Limit of quantitation X
2004.10.20 Dr. Pogány - WHO, Bangkok 38/49
 CLEANING VALIDATION
Potential contaminants
 Product residues
 Cleaning agent residues
 Airborne matter
 Lubricants, ancillary material
 Decomposition residues
 Bacteria, mould and pyrogens

2004.10.20 Dr. Pogány - WHO, Bangkok 39/49

 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

2004.10.20 Dr. Pogány - WHO, Bangkok 40/49

 VISUALLY CLEAN
 Always first criterion
 Can be very sensitive but needs verification
 Use between same product batches of same
formulation
 Illuminate surface
 Spiking studies

2004.10.20 Dr. Pogány - WHO, Bangkok 41/49

 NOT MORE THAN 0.1%
 APIs are often considered to be non-active at 0.1 of their
normally prescribed dosages.
 Need to identify worst case (least water-soluble, most
toxic API)
 One should identify the equivalent of 0.1% of the lowest
therapeutic dose of the most toxic product to be cleaned
away. No more than this 0.001 of a dose should be
detectable in the largest daily dose of the product being
manufactured subsequently in the same equipment.

2004.10.20 Dr. Pogány - WHO, Bangkok 42/49

 10ppm
 This criterion requires that there be no more than
10 ppm of the cleaned compound in the next
product to be manufactured.
 Assumes residue to be harmful as heavy metal
 Useful for materials for which no available
toxicological data
 Not for pharmacologically potent material

2004.10.20 Dr. Pogány - WHO, Bangkok 43/49

 LITERATURE METHODOLOGY (1)

Product 2 Product 2
Product Product Product
(low (high
1 3 4
strength) strength)
Smallest strength (mg) 50 15 15 200 1000
Maximum dosing (units/day) 1 6 3 4 8
Batch size (units/lot) 40,000 65,000 90,000 30,000 35,000
Unit weight (mg) 400 200 400 500 750
Batch size (kg/lot) 16 13 36 15 26

2004.10.20 Dr. Pogány - WHO, Bangkok 44/49

 LITERATURE METHODOLOGY (2)
Product 2 Product 2
Product Product Product
(low (high
1 3 4
strength) strength)
Surface area
Equipment Use
(in.2)
Sieve 2000 X X
Mill 1000 X X
Mixer 3000 X X X X X
Press 1500 X X X X X
Coater 2000 X X

2004.10.20 Dr. Pogány - WHO, Bangkok 45/49

 HYPOTHETICAL EXAMPLE
0.1% dosis criterion (mg in 4-in.2 swab area)

FPP 2LD 2HD 3 4

1 0.481mg 0.923mg 0.333mg 0.194mg

10 ppm criterion (mg in 4-in.2 swab area)

FPP 2LD 2HD 3 4
1 0.116mg 0.222mg 0.133mg 0.233mg

Visibility criterion: 0.100mg in 4-in.2 swab area

2004.10.20 Dr. Pogány - WHO, Bangkok 46/49
 LITERATURE SOURCE
Cleaning Validation and Residue Limits: A Contribution
to Current Discussions[1]
Andreas O. Zeller, Dr phil. nat., is manager of the
quality assurance department for the quality planning
and testing of initial materials at Sandoz AG,
Deutschhermstrasse 15, Postfach, W-8500 Nürnberg 1,
FRG, tel. +49 911 273 0, fax +49 911 27 38 02.
[1] Published in Pharmaceutical Technology Europe,
October 1993

2004.10.20 Dr. Pogány - WHO, Bangkok 47/49

 BEST PROCESS
MINIMUM REQUIRED INPUT

MAXIMUM OUTPUT

AT NO COST TO SOCIETY (industrial

safety, labour safety, internal and external
environment protection)

2004.10.20 Dr. Pogány - WHO, Bangkok 48/49

 COSTS OF QUALITY
Visible 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.

2004.10.20 Dr. Pogány - WHO, Bangkok 49/49