Facility and AHU Validation
Facility and AHU Validation
Facility and AHU Validation
for
• US FDA www.fda.gov
21 CFR
Part 210 cGMP in Manufacturing, Processing, Packing or Holding of Drugs
Part 211 cGMP for Finished Pharmaceuticals
Center for Drug Evaluation and Research, US FDA
• PDA www.pda.org
• WHO
Facility and AHU Validation
Validation
• Production processes
• Cleaning Procedures
• Analytical methods
• In-process control test procedures
• Computerised systems
• Personnel
• Responsibilities
• Standards
• Content / Guidance
• Schedule of work
alidation Master Plan ( VMP )
art A – Organisation and Scope
Introduction
Managerial Responsibilities
10 Structure of Support Data files
1 Quality Assurance Manager
2 Operations Manager 11 Documentation Control and Archiving
3 Validation Document Preparations and Authorisation
12 Change control
Validation Phases
Part B – General Validation Standards and
1 Design Qualification Guidelines – List of Guidelines
2 Installation Qualification
3 Operation Qualification
Part C – Schedule of Validation Actvities
4 Performance Qualification
Validation Standards and Guidelines ( Examples )
• Qualification records
• Maintenance contracts
• Daily calibration
Qualifications
Use of any Equipment or System and is usually carried out by conducting the following :
Design Qualification ( DQ )
Documented evidence and verification that the proposed design of the equipment or system is suitable for the intended use
Installation Qualification ( IQ )
Documented evidence and verification that the equipment or systems, as installed or modified, comply with the approved
design and the manufacturer’s recommendations.
Operational Qualification ( OQ )
Documented evidence and verification that the equipment or systems, as installed or modified, perform as intended
throughout the anticipated operating ranges
Performance Qualification ( PQ )
Documented evidence and verification that the equipment and ancillary systems, as connected together, can perform
effectively and reproducibly based on the approved process method and Specifications
Retrospective Qualification ( RQ )
Applicable only for ancient equipment or systems which have not undergone the four steps above. It is documented
evidence and verification that the equipment or systems is suitable for the intended use, and perform as intended
Calibration
Demonstration, that a particular instrument or device produces results within specified limits
by comparison with those produced by a reference or traceable standard over a appropriate
range of measurement
Maintenance
The documented evidence that a particular Instrument is properly cleaned, repaired and
checked for any potential malfunction at regular intervals of time
Building and Facility
Criteria –
• Location selection
• Design ( Flow of Man and material )
• Ease of cleaning, Maintenance,
• Ease of Operation
• Minimise potential Contaminations ( different stages , Microbial )
• Adequate space for Equipment and Material to prevent mixup
Design and Construction
• Aseptic Processing
• Floors, walls and ceilings of smooth , hard surfaces are easily cleanable
• Air supply filtered through HEPA under +ve pressure ( laminar and Non-laminar)
Adequate ventilation
Equipment for control over air pressure, micro-organism, dust, humidity and
temperature
Sewage, trash and other refuge should be disposed of in a safe and sanitary manner
Building used for the manufacture, processing, packing or holding of a drug shall be
maintained clean and in good sanitary condition
To facilitate operations for the intended use and for its cleaning and maintenance
Construction
Surface should be not reactive, add or absorb so as to alter the safety, identity,
strength, quality or purity of the drug product beyond official or established requirement
Written procedure shall be established and followed for cleaning and maintenance
Assigning responsibilities
Schedule
Details of the method, equipment and material used
Instructions for disassembling and reassembling each article of equipment
to ensure proper cleaning
Removal or defacing previous batch identification
Protection of clean equipment from contamination prior to use
Inspection of equipment for cleanliness immediately before use
Records of the work done
Automatic, mechanical and electronic Equipment
• Input to and output from computers or related systems of formulas or other records
should be checked for accuracy
Commercially available software does not necessarily require the same level
of validation as a customised software.
If an existing system was not validated at time of installation, a retrospective
validation could be conducted if appropriate documentation is available.
Computerized systems should have sufficient controls to prevent unauthorized
access or changes to data. There should be controls to prevent omissions in
data (e.g., system turned off and data not captured). There should be a record
of any data change made, the previous entry, who made the change, and
when the change was made. ( 21 CFR Part 11 )
Computerized Systems
These records should demonstrate that the system is maintained in a validated state.
If system breakdowns or failures would result in the permanent loss of records,
a back-up system should be provided. A means of ensuring data protection should be
established for all computerized systems.
Containment
Dedicated production areas for -
Highly sensitising materials.
Eg. Penicillins or Cephalosporins
Acceptance criteria for residues and the choice of cleaning procedures and
cleaning agents should be defined and justified.
HEPA :
High Efficiency Particulate Absolute Air Filter. This is a 0.3 µm filter
made from cellulose fiber and is the heart of a Clean room.
ACPH :
Air Changes Per Hour. It is the number of times, the air within
the Clean room is completely replaced.
2. Filter positions
0,30 m/s
Annex 1, 17.3
Module 3, Part 3: Design, qualification and maintenance Slide 3 of 27 WHO - EDM
Air flow patterns (2)
Turbulent
Uni-directional ( Laminar )
GMP aspect
Economical aspect
Main filter
1 2 3
HEPA Filter
AHU
Main filter
Ceiling
exhausts
1 2 3
AHU
Prefilter
1 2
Or
• a proportion re-circulated
GMP aspect
Economical reasons
Air Handling Systems
Ventilation with 100% fresh air (no air re-circulation)
Washer (optional)
Exhaust Unit
Production Rooms
Annex 1, 17.24
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installation is complete with all equipment installed and operating, with specified number of
services connected and
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production equipment,
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Qualification / Validation issues
Process validation
Adequate documentation
Qualification ( OQ, PQ ) ( 1 )
Uni-directional Turbulent /
Test airflow/ LAF Mixed airflow
Description
Parallelism 2 N/A
Air flow pattern 2 3
Uni-directional Turbulent /
Test airflow/ LAF Mixed airflow
Description
air
Sampling point
Microbiological validation
Design condition
What are the alert and action Limits and what procedures are followed if these points are exceeded ?
Clean room monitoring program (2)
Shutdown
Federal Standard 209 E Class ISO 14644 – 1 Class Air Changes Per Hour
Eg:
ISO Class 1 10 2
Note: Uncertainties related to the measurement process require that concentration data with no more than three significant figures be used in determining the
classification level.
Cleanroom maintenance program (1)
Corridors > Air lock > Change room > Wash room
(++++) (+++) (++) (+)
Process areas Ante room
(++) (+)
Operating procedures
Maintenance records
A ir S h o w e r
Group
Typical Session
Clean room layout
( c o n t a in s V a c u u m & R O w a t e r s u p p ly )
W a re h o u se
W e ig h in g T a b le t 1 T a b le t 2 L iq u id s M ix S o ftg e l C a p su le
A ir L o c k 2
P a c kin g
A / Lock 1
C le a n C o rri d o r
E m erge nc y
E x it
M a le F e m a le
2 S ta g e Change 2 Change 2
S te rile e y e d ro p s p e rso n n e l P rim a ry & S e c o n d a ry
d isp e n sin g e n try fo r P a c ke d
P a c kin g
& a c e p tic fillin g e y e d ro p s G oods
A ir L o c k 3
Q u a ra n tin e
M a le F e m a le
Change 1 Change 1
E q u ip m e n t W a sh A ir L o c k 4
S e rv ic e R o o m
Modified
Group Clean
Session room layout
– modified layout
30P a ( c o n t a in s V a c u u m & R O w a t e r s u p p ly )
A ir S h o w e r
20P a 30P a
10P a
W e ig h P o st
B o o th S ta g in g S o ftg e l C a p su le
W a re h o u se
M AL 2 20P a 30P a T a b le t 1 T a b le t 2 L iq u id s M ix P a c kin g
15P a 15P a 30P a
0P a
A ir L o c k
M A L1
15P a
30P a
C le a n C o rri d o r
E m erge nc y
E x it
20P a 20P a
P AL
40P a M a le F e m a le 10P a
M A L 3 Change 2 Change 2 S e c o n d a ry P rim a ry
S te rile e y e d ro p s P a c kin g P a c kin g
40P a d isp e n sin g P a c ke d
& a sc e p tic fillin g G oods
Q u a ra n tin e 20P a 30P a
10P a 10P a
60P a
Change M a le F e m a le
15P a M A L 4
50P a Change 1 Change 1
E q u ip m e n t W a sh 50P a A ir L o c k 4
S e rv ic e R o o m 0P a
0P a
0P a