Validation Part2

Validation | Slide 1 of 48 August 2006

Validation

Supplementary Training Modules on Good Manufacturing Practice

WHO Technical Report Series, No. 937, 2006. Annex 4.


ValidationValidation

Part 1. General overview on qualification and validation

Part 2. Qualification of HVAC and water systems

Part 3. Cleaning validation

Part 4. Analytical method validation

Part 5. Computerized system validation

Part 6. Qualification of systems and equipment

Part 7. Non sterile product process validation


Qualification of HVAC and water systems

Part 2


WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 1 and 2


HVACHVAC

Objectives

To understand key issues in – commissioning, – qualification and – maintenance of

HVAC and Water systems

8.


Description of design, installation and functions

Specifications, requirements

Manuals

Operating procedures

Instructions for performance control, monitoring and records

Maintenance instructions and records

Training of personnel

― programme and records

Documentation requirements to assist in commissioning, qualification and maintenance

HVAC


HVACHVAC

Commissioning

Precursor to qualification

Includes setting up, balancing, adjustment and testing of entire HVAC system to ensure it meets requirements in URS and capacity

Acceptable tolerances for parameters

Training of personnel

8.1.1, 8.1.4, 8.1.5


HVACHVAC

Commissioning (2)

Records and data maintained include:

Installation records – documented evidence of measure capacities of the system

Data: design and measurement for, e.g. air flow, system pressures

O&M manuals, schematic drawings, protocols, reports

8.1.2, 8.1.3, 8.1.6


HVACHVAC

Qualification

Validation is an extensive exercise

Qualification of the HVAC system is one component in the overall approach that covers premises, systems/utilities, equipment, processes, etc.

See also full guidelines on "Validation" in WHO TRS, No. 937, 2005, Annex 4

Risk based approach for HVAC qualification

8.2.1


HVACHVAC

Qualification (2)

Described in a Validation Master Plan (VMP)

VMP to include the nature and extent of tests, and protocols

DQ, IQ, OQ, and PQ

Risk analysis to determine critical and non-critical parameters, components, subsystems and controls

8.2.2 – 8.2.5


HVACHVAC

Qualification (3)

Direct impact components and critical parameters should be included

Non-critical systems and components are subjected to Good Engineering Practices (GEP)

Acceptance criteria and limits defined in design stage

Design conditions, normal operating ranges, operating ranges, alert and action limits

8.2.5 – 8.2.11


HVACHVAC

Design conditions and normal operating ranges set to achievable limits

OOS results recorded

8.2.12 – 8.2.15

A C TIO N LIM IT

A LERT LIM ITA LERT LIM IT

A C TIO N LIM IT

O perating Range - Validated Acceptance Criteria

Norm al O perating Range

Design Condition


HVACHVAC

Qualification – examples of aspects to consider

DQ – Design of the system, URS

– (e.g. components, type of air treatment needed, materials of construction)

IQ – Verify installation

– E.g. relevant components, ducting, filters, controls, monitors, sensors, etc.

– Includes calibration where relevant


HVACHVAC

Qualification (4)

Typical parameters to be included in qualification (based on risk assessment):

Temperature

Relative humidity

Supply, return and exhaust air quantities

Room air change rates

Room pressures (pressure differentials)

8.2.17


HVACHVAC

Qualification (5)

Typical parameters to be included in qualification (based on risk assessment) (2):

Room clean-up rate

Particulate matter, microbial matter (viable and non-viable)

HEPA filter penetration tests

Containment system velocity

Warning/alarm systems

8.2.17


HVACHVAC

Qualification (6)

Conduct of the tests:

Time intervals and procedure to be defined by the manufacturer

Influenced by the type of facility and level of protection

See also ISO 14644 for methods of testing

Requalification, and change control

8.2.18 – 8.2.20, 8.2.9


HVACHVAC

Qualification (7)

Tests performed according to protocols and procedures for the tests

Results recorded and presented in report (source data kept)

Traceability, e.g. devices and standards used, calibration records; and conditions specified


HVACHVAC

Schedule of tests to demonstrate continuing compliance

*Test procedure as per ISO 146448. Table 3

Test ParameterObjectiveMaximum time interval

Test procedure* and key aspects

Particle count testVerifies cleanliness6 months or 12 months depending on Class

Particle counter. Readings and positions

Air pressure difference

Absence of cross-contamination

12 monthsMeasure pressure difference

Airflow volumeVerify air change rates

12 monthsMeasure supply and return air, calculate air change rate

Airflow velocityVerify unidirectional airflow and or containment condition

12 monthsVelocity measurement


HVACHVAC

Recommended optional strategic tests

*Test procedure as per ISO 146448. Table 3

Test ParameterObjectiveMaximum time interval

Test procedure* and key aspects

Filter leakageVerify filter integrity12 monthsFilter media and filter seal integrity

Containment leakageVerify absence of cross-contamination

12 monthsAirflow direction and pressure differential

Recovery (time)Verify clean-up time12 monthsTime taken maximum 15 minutes

Airflow visualizationVerify required airflow patterns

12 monthsAirflow direction, documented evidence


Cleanroom monitoring programme (1)

Routine monitoring programme as part of quality assurance

Additional monitoring and triggers, e.g.

1. Shutdown

2. Replacement of filter elements

3. Maintenance of air-handling systems

4. Exceeding of established limits

HVAC


Cleanroom monitoring programme (2)Particles and Microbiological contaminants

Number of points/locations for monitoring determined, specified, documented in procedure and or protocol

Sufficient time for exposure, and suitable sample size Identification and marking of sampling points Definition of transport, storage, and incubation conditions Results to reflect the procedure/protocol followed Define alert and action limits as a function of cleanliness

zone/class

HVAC

See also ISO 14644


air

Example of a sampling point

Cleanroom monitoring programme (3)

Cleanrooms should be monitored for microorganisms and particles

HVAC


Definition of Conditions

air

as built

air air

at rest in operation

HVAC


Qualification – examples of aspects to consider in qualification (OQ, PQ)

Test

Differential pressure on filters

Turbulent / mixed airflow

Description Uni-directional airflow / LAF

Room differential pressure

Airflow velocity / uniformity

Airflow volume / rate

Parallelism

Airflow pattern

2 2

N/A 2, 3

2, 3 Optional

2 2

2 N/A

2 3

1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)

3 = Operational (ideally used to perform PQ)

HVAC


Test Turbulent /

mixed airflow Description

Uni-directional airflow / LAF

Recovery time

Room classification (airborne particle)

Temperature, humidity

N/A 2

2 2,3

N/A 2,3

1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)

3 = Operational (ideally used to perform PQ)

HVAC

Qualification – examples of aspects to consider in qualification (OQ, PQ)


HVACHVAC

Maintenance

Procedure, programme and records for planned, preventative maintenance

– e.g. Cleaning of filters, calibration of devices

Appropriate training for personnel

Change of HEPA filters by suitably trained persons

Impact of maintenance on:– Product quality– Qualification

8.3.1 – 8.3.5


Verification of design documentation, including description of installation and functions specification of the requirements

Operating procedures Maintenance instructions Maintenance records Training logs Environmental records Discussion on actions if OOS values On site verification (walking around the site)

Inspecting the air-handling system

HVAC


Air-handling systems:

Play a major role in the quality of pharmaceuticals Should be designed properly, by professionals Should be treated as a critical system

Conclusion

HVAC


This series of explanations will now be followed by:

Group discussion, with a simple exercise Short test

Further proceedings

HVAC


Group Session

S e rv i c e R o o m

W a re h o u se

A/ Lo

ck 1

Air L

ock 2

A i r S h o w e r

S a m p l i n gR o o o m S e rv i c e C o rr i d o r

(contains V acuum & RO water supply)

W e i g h i n g T a b l e t 1 T a b l e t 2 L i q u i d s M i x S o f t g e l C a p su l eP a c ki n g

Em ergencyExit

C l e a n C o rr i d o r

E q u i p m e n t W a sh

A i r L o c k 3

S t e ri l e e y e d ro p sd i sp e n si n g

& a c e p t i c f i l l i n g

2 S t a g ep e rso n n e l

e n t ry f o re y e d ro p s

M a l eC h a n g e 2


F e m a l eC h a n g e 1


P a c ke dG o o d s

Q u a ra n t i n e

A i r L o c k 4

P ri m a ry & S e c o n d a ryP a c ki n g

HVAC


Group Session – modified layout

S e c o n d a ryP a c ki n g

30P a

0P a

20P a 30P a

0P a0P a

10P a

10P a 10P a

20P a20P a

40P a

50P a

60P a

50P a

40P a

15P a

15P a

P ri m a ryP a c ki n g

C h a n g e

M A L 3

A i r L o c k

30P a

P o stS t a g i n g

30P a

30P a

0P a

15P a15P a

20P a

20P a

30P a

20P a

0P a

10P a

S e rv i c e R o o mA i r L o c k 4

P a c ke dG o o d s

Q u a ra n t i n e





P A L

S t e ri l e e y e d ro p sd i sp e n si n g

& a sc e p t i c f i l l i n g

M A L 4

E q u i p m e n t W a sh

C l e a n C o rr i d o rEm ergency

Exit

S o f t g e l C a p su l eP a c ki n gL i q u i d s M i xT a b l e t 2T a b l e t 1

W e i g hB o o t h

(contains V acuum & RO water supply)S e rv i c e C o rr i d o r

S a m p l i n gR o o o m

A i r S h o w e r

MAL

2

MAL

1

W a re h o u se

MAL = Material Air LockPAL = Personnel Air Lock

HVAC


Commissioning, Qualification and

validation of Water systems


WHO Technical Report Series No 929, 2005. Annex 3


HVACHVAC

Objectives

To understand key issues in – commissioning, – qualification and – maintenance of

HVAC and Water systems

7.


Objectives

To discuss the operational considerations of water systems including:

Start up, commissioning and qualification

Monitoring

Maintenance

System reviews

Water for Pharmaceutical Use

7.


Start up and commissioning

Precursor to qualification and validation

Should be planned, well defined, well documented

Includes setting to work

Includes system set-up

Includes recording of system performance parameters

Controls loop tuning


7.1


Qualification

WPU systems are "direct impact systems"

Therefore stages to be considered in qualification should include DQ, IQ, OQ, PQ

DQ: Design review influenced by source water and required water quality

IQ: Installation verification of the system


7.2


Qualification

OQ: operational qualification

Presentation focusing on PQ

PQ demonstrates consistent and reliable performance of the system

Three phase approach recommended over extended period – proves reliability and robustness


7.2


Phase 1 (1)

A test period of 2–4 weeks - monitoring the system intensively

System to operate continuously without failure or performance deviation

The following should be included in the testing approach:

Undertake chemical and microbiological testing in accordance with a defined plan


7.2


Phase 1 (2)

Sample daily:– incoming feed-water– after each step in the purification process– each point of use and at other defined sample points

Develop:– appropriate operating ranges– and finalize operating, cleaning, sanitizing and maintenance

procedures


7.2


Phase 1 (3)

Demonstrate production and delivery of product water of the required quality and quantity

Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting

Verify provisional alert and action levels

Develop and refine test-failure procedure


7.2


Phase 2 (1)

A further test period of 2–4 weeks – further intensive monitoring the system

Deploying all the refined SOPs after the satisfactory completion of phase 1

Sampling scheme generally the same as in phase 1

Water can be used for manufacturing purposes during this phase


7.2


Phase 2 (2)

Demonstrate:

Consistent operation within established ranges

Consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs.


7.2


Phase 3

Over one year after the satisfactory completion of phase 2

Water can be used for manufacturing purposes during this phase

Demonstrate:– extended reliable performance– that seasonal variations are evaluated

Sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2


7.2


Ongoing system monitoring

After Phase 3 – system review needed

Based on review including results, establish a routine monitoring plan

Monitoring to include a combination of on-line monitoring and off- line sample testing

Data analysed for trends


7.3


Ongoing system monitoring (2)

Monitoring parameters to include:– flow, pressure, temperature, conductivity, TOC

Samples taken:– From points of use, and specific sample points – In a similar way how water is used in service

Tests to include physical, chemical and microbial attributes


7.3


Maintenance

A controlled, documented maintenance programme covering:

Defined frequency with plan and instructions

Calibration programme

SOPs for tasks

Control of approved spares

Record and review of problems and faults during maintenance


7.4


System review

WPU (PW, HPW and WFI) systems to be reviewed at appropriate regular intervals

Review team includes engineering, QA, operations and maintenance


7.5


System review (2)

The review to cover, e.g.– changes made since the last review;– system performance; – reliability;– quality trends;– failure events;– investigations;– out-of-specifications results from monitoring;– changes to the installation;– updated installation documentation;– log books; and– the status of the current SOP lists


7.5


ValidationValidation

Group session

Documents

Validation Part2