TEVA Quality Standard Manual

Chapter 4 – Facilities, Critical Systems and Equipment

4.1 General

4.1.1 Facilities, manufacturing support systems, equipment and instrumentation must

meet cGMP while complying will all other governing local codes, laws and
regulations.
For sterile manufacturing operations, see additional requirements in Chapter 10.

4.1.2 The design, installation, qualification/validation and ongoing maintenance of these

facilities, systems and equipment are the primary responsibility of the Engineering
Department.

4.1.3 A systematic and documented approach for all facilities, systems and equipment is
required to assure that they perform in accordance with their design criteria and
within their operating ranges. An engineering document shall follow a clear
template, be simple and contain only relevant information, shall be updated,
available and accessible to all who might require the information contained in it.
This document shall be subject to the change control procedure.

4.1.4 The basis for a facility construction, systems and equipment installation is included
in the User Requirements Specification (URS), a document prepared by the
Engineering Department and approved by Production, QA, and R&D. The URS
also serves as the base document for preparing the commissioning and validation
protocols. The URS shall include a systematic list of requirements, such as
operational functional range, controls, safety, construction materials, construction
procedures, drawings and documentation to be supplied and applicable standards,
and GMP concerns in the design and construction of facilities, systems and
equipment.

Suppliers and contractors shall be qualified and approved by the Engineering

Department.

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4.1.5 An approved list of systems and equipment with approved drawings and unique
identification numbers shall be maintained. Systems and equipment “trees” shall
include all instrumentation installed, identified with a unique number. The list,
drawings and trees form the basis for the calibration and validation programs.

4.2 Facilities

4.2.1 General
4.2.1.1 The facility must be located, designed, constructed and maintained to best

suit the specific operation to be carried out in it, as well as to ensure

compliance with applicable regulations. The facility design and the
construction, as well as the construction materials and finishes shall provide
adequate flows of materials and personnel in order to prevent mix-ups and
facilitate effective cleaning while minimize contamination and cross-
contamination.

4.2.1.2 All operations shall be performed in designated areas of adequate size and

separated as follows to ensure adequate control of materials and processes:

• Receiving and storage area for raw materials and packaging

components
• Restricted access storage areas for labeling materials (*)
• Sampling area
• Holding of rejected materials and components until disposition (*)
• Weighing, dispensing and staging of dispensed materials
• Manufacturing operations
• Packaging operations
• Storage of in process and finished products (*)
• Quality Control laboratories
• R&D laboratories
(*) The requirement for separation is not applicable, when a validated automated
warehousing system exists.

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4.2.1.3 In addition certain ancillary, non-production areas, shall be available in

each facility (changing rooms, washing and toilets, maintenance, canteen,

etc.)

4.2.1.4 For the manufacture of certain pharmaceutical products, such as highly

sensitizing materials (e.g. penicillins) or biological preparations and certain

products such as cephalosporins, sex hormones and analogs, cytotoxics or
other highly active drugs, dedicated and self-contained facilities must be
available. Pesticides and herbicides are not allowed to be manufactured in
the premises and equipment used for the manufacture of medicinal
products.

4.2.1.5 A vermin and pest control program shall be in place, using as far as

possible, mechanical or sticky devices, instead of chemicals. When

pesticides or rodenticides are used, care shall be taken to avoid personnel or
material contact.

4.2.1.6 Manufacturing areas may be classified in four areas. Areas 1 to 3 have

defined environmental conditions, corresponding to the degree of

cleanliness and hygiene required.

Area 1 - Full product exposure, e.g. granulation, tabletting, coating,

encapsulation

Area 2 - Reduced or partial exposure of product in areas, where product

containers are opened during connection to equipment.

Area 3 - No product exposure, e.g. transport and staging.

Area 4 - Technical areas, where no products or containers are present. This

area is not in the scope of the HVAC System

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4.2.2 Storage and Sampling areas

4.2.2.1 Storage areas shall be designed with sufficient capacity to allow the storage

of materials, products and components according to the inventory policy.

The areas shall be easily cleaned and capable of maintaining temperature
and, if necessary, relative humidity within the recommended storage
conditions (see Table's 4 and 5), which shall be continuously monitored
and trended. Mean kinetic temperature (MKT) may be used in assessing
cases of temperature spikes.

4.2.2.2 Receiving and transient shipping areas shall be adequately designed to

protect materials and products from the weather and external contamination.

4.2.2.3 The height of the lowest pallet shelf in the racks and the distance of pallets

to the walls shall be such as to allow easy cleaning. When pallets sit directly
on the floor, they must be moved periodically to allow cleaning underneath.

4.2.2.4 Commingling of materials with different statuses is prohibited. Where a

physical quarantine status policy is adopted, the area must be clearly

marked and access restricted to authorized personnel only. Any other
quarantine system shall be validated to provide equivalent security.

4.2.2.5 Separate, controlled sampling areas for raw materials, packaging

components and labeling shall be provided and the sampling operations
shall be conducted in a way that prevents uncontrolled material exposure
and cross-contamination. The sampling area for raw materials shall be
entered through an air lock. The sampling area and the airlock shall be
pressurized to the environment and inlet air shall be filtered to the same
degree as in production. The airlock shall be under the highest pressure to
prevent both outward material contamination and inward external
contamination.

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4.2.2.6 Segregated areas shall be provided for the following items, unless a

validated automated system is in place:

• Rejected and recalled materials and products
• Returned materials and products
• Printed packaging materials (labeling)

4.2.2.7 Controlled drug substances and products must be kept in a separate, secured

area under the control of authorized personnel, and provided with alarms.

4.2.3 Production areas

4.2.3.1 Production areas shall be laid out in a logical order to the operation

sequences and provide the required cleanliness levels, to avoid

contamination and cross-contamination and in a way that minimizes the risk
of mix-ups, confusions, omissions or erroneous performance of any of the
manufacturing and control steps.

4.2.3.2 Rooms where product components are exposed to the environment shall

have smooth surfaces and crack free walls, floors and ceilings, easy to clean
and if necessary to be sanitized and disinfected.

4.2.3.3 Support system components (pipe work, light fittings, ventilation openings

etc.) shall be designed and installed in a way that avoids the creation of
recesses which are difficult to clean. It is recommended that whenever
possible, the maintenance of these components to be performed from
outside the manufacturing area.

4.2.3.4 Drains shall be of adequate size and equipped with atmospheric air breaks,

of not less than 50 mm.

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4.2.3.5 The ventilation and air conditioning parameters (HVAC capacity) shall be

in each case adapted to the product requirement for temperature and relative
humidity and to the external environment. The inlet and outlet air shall be
properly filtered to meet product and environment quality requirements (see
Tables 4 and 5).

4.2.3.6 When, during production steps, dust is generated, suction and dedusting

devices shall be used to minimize the occurrence. The “containment”

approach of isolating the process step is recommended, wherever feasible.

4.2.3.7 Lighting appropriate to the activities performed shall be provided.

4.2.4 Quality Control Areas

4.2.4.1 Quality Control and in-process laboratories shall be separated from the

production areas. In particular, biological and microbiological laboratories

shall not be adjacent to manufacturing and storage areas.

4.2.4.2 Measures shall be taken to protect sensitive equipment from vibration,

humidity and electrical interference.

4.2.4.3 Adequate and sufficient space shall be provided for laboratory glassware,

reagents, sample storage, records etc.

4.2.4.4 Isolated areas with adequate safety provisions shall be provided for highly

potent product testing.

4.2.5 Ancillary Areas

4.2.5.1 Changing rooms, washing facilities, toilets and other social areas shall be

provided at each facility, appropriate to the number of employees and with

easy access from the production. Toilets shall not be adjacent to production
or storage areas.

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4.2.5.2 Maintenance, energy centers, workshops shall not be in close vicinity to

manufacturing and storage areas. Whenever machine components and spare

parts are stored/handled in the production area, they shall be kept in lockers
or rooms specially designated for this purpose.

4.3 Systems

Systems are categorized as Critical Systems, Support Systems, and Utility Systems.

4.3.1 Critical Systems

Critical systems are those which contact the product and/or materials. Being
critical, they shall be designed, constructed, commissioned and validated
accordingly.

The typical critical systems are the Water Systems, Clean Steam, the Heating,
Ventilating and Air Conditioning System (HVAC), the Compressed Air System
(CAS) and other compressed gas systems, the Clean-In-Place (CIP) and
Sterilization-In-Place (SIP) systems. The electrical alarm system for the storage of
controlled substances is also considered as critical.

Critical parameters shall be controlled and continuously monitored and visual,

audio and/or computerized alarms should be set off after a time delay appropriate to
the parameter measured.

For complete details on this subject, please read Global Corporate Policy 50.29.09 "Alarm
Delays for Critical Parameters."

4.3.2 Support Systems

Support systems are those which directly support the process operations, but do not
contact the product or materials. They include the Heating and Cooling, Vacuum

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and Potable Water systems and are designed, constructed and commissioned,
according to applicable codes and standards.

Support systems are deemed non-critical. Their effect upon the manufacturing
processes shall be considered from an operational point of view.

4.3.3 Utility Systems

Utility systems are those which do not contact the product or materials and are
general site or building systems, not tailored only to the manufacturing. Utility
systems are deemed non-critical and include the Industrial Steam, Drainage, and
Chilled Water for the HVAC System and Fire Extinguishing Systems. They are
designed, constructed and commissioned, according to applicable codes and
standards.

Note: Similar Systems within a facility could have multiple categorizations. If compressed air is
used as instrument air, it is defined as a Utility System. If used to operate tablet presses in a way
that it can affect the tablet press compression pressure it is defined as a Support System. If used to
dry a product equipment contact surface, it is defined as a Critical System.

4.3.4 Purified Water (PW)

4.3.4.1 General

The design, construction, commissioning and validation of the Purified

Water System (PWS) shall be performed according to cGMP, based on an
approved Engineering File.

Purified Water shall meet USP and/or EP and additional requirements (see
Tables 1, 2 and 3). Purified water shall be used for compounding, for the
final rinse in non-sterile equipment cleaning and may be used, followed by
Water for Injection, for initial rinse of sterile equipment cleaning.

4.3.4.2 Basis for Design

The following construction materials and methods, and operating principles

are applied to maintain the required PW quality.

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(1) Materials
• The following materials shall be used:
- Type 316L stainless steel for all components that are to be welded in

the field, and cannot be annealed after welding.

- Type 316 stainless steel may be used for components that are
annealed after welding.
- Other inert synthetic materials approved for food contact.
- Gaskets made of materials approved for food contact.

• Internal surfaces of equipment and components are mechanically

polished to a minimum of 180 Grit, followed by electro-polishing to
provide a smooth surface and to assist in inspection.
• Documentation identifying the materials and their approval for food
contact shall be maintained.

(2) Construction
• Piping is welded wherever possible. Welding is performed by using
fully automatic orbital welding techniques. Welding quality shall be
assured and documented by a suitable inspection procedure.
• The design and construction eliminate or at least minimize dead legs.
• Unused portions of the piping are kept to a minimum, and in no case
shall exceed 3 times the internal diameter of the branch line.
“Unused” is defined as a portion of the piping that is not flushed at
least once every 24 hours.
• The system is slopped and fully drainable.
• All drainage points are provided with atmospheric air breaks. The
minimum required air gap is 50 mm, measured above the flood
level rim of the drain or curbed area.
• Check valves are provided for back flow prevention, in all instances
of cross connection with other systems .

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(3) Equipment and Components

• The storage tank is equipped with a man way to permit access for
inspection.
• The storage tank is sealed and is equipped with a vent filtration
system to exclude airborne microorganisms and particulate matter.
• The vent filter shall be of the type suitable for pharmaceutical
applications: antibacterial, hydrophobic, 0.2 µ pore size. The vent
filter is prevented from becoming wet during operation by
continuous heating and there is no hold-up area in the piping. High
and low temperature alarms, independent of the heating temperature
control, shall be provided.
• There are no filters in the piping system, between the storage tank
and the points of use.
• The pump is of a sanitary type, supplied with mechanical seals, and
the water being pumped is used as the seal lubricant.
• The heat exchangers are of the double tube sheet type.
• The pipes, piping components and the valves are of a sanitary
design.
• Sanitary clamp type fittings are used for connections to other
systems and equipment and in order to facilitate maintenance.

(4) Operating Principles

• Water is permanently re-circulated through the storage tank and
distribution loop.
• The distribution loop is maintained under continuous positive
pressure, to ensure continuous flow of water through the distribution
loop at all times, even in case of no demand, and in order to ensure
supplying water to washing machines, at the minimum pressure
needed. The desired pressure is measured at the end of the
distribution line.

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• The entire system is subjected to adequate cleaning, passivation and

heat sanitization programs .
• There is provision for sampling the water upstream and downstream
of all components that could affect the microbiological or chemical
quality of the water.
• The following parameters are defined as critical and provided with
control, on line monitoring, and alert and action alarms functions:
conductivity, TOC, temperature, vent filter temperature, pressure.

4.3.4.3 Monitoring Program:

For complete details on this subject, please read Global Corporate Policy 50.29.12 "Testing of
High Purity Water."

Periodic monitoring shall be performed and results analyzed for trends.

Samples are taken from a number of sampling and users’ points, on a
rotational basis to cover all outlets.

Table 1 - Testing Frequency

Water System Frequency Tests
Chemical Microbiological
1. Potable Water Monthly --

2. Softened Water Monthly --

3. Purified Water Monthly --
Generation
4. Purified Water Daily Conductivity
Storage & Distribution TOC
Weekly - Total count
Pseudomina aeruginosa
Monthly Full monograph

Table 2 – Chemical Tests

Water System Test Alert Action
Purified Water Conductivity N/A 1.3 µS/cm at 25°C
Storage
& Distribution TOC N/A 500 ppb
Full N/A USP and/or Ph. Eur.
monograph

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Table 3 - Microbiological Tests - Alert and Action Levels

Water System Test Alert (CFU/ml) Action (CFU/ml)
1. Potable Water Total count 10 50
Coliforms N/A 1/100 ml
2. Softened Water Total count 10 50
3. Purified Water Generation Total count 10 50
4. Purified Water Total count 10 50 *
Storage & Distribution
Pseudomonas N/A 1/100 ml
aeruginosa
* Representative colonies from all plates must be identified. Attention must be paid to unusual or objectionable microorganisms.
The impact of the contaminant on product quality shall be assessed by Quality Assurance.

4.3.5 HVAC

4.3.5.1 General

HVAC is a direct impact system; its failure to perform may directly affect
product quality and/or operator safety. In order to maintain a protected or
controlled environment, the following concerns are considered:
• Cross contamination minimization
• Protection of products from particulate and microbiological
contamination
• Product properties and characteristics (e.g. hygroscopicity)
• Operator safety and comfort
• Environmental protection

The HVAC parameters, which may affect product quality and/or operator
safety are:
• Temperature
• Relative humidity
• Air flow patterns
• Air balance and air changes
• Microbial contamination

4.3.5.2 Basis for Design

• Air handling must be balanced. The air supply and return from each air
handling unit must be established.

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• Air in the facility should be 100% outside fresh air. When air is re-
circulated, HEPA filtration shall be provided for in the return ducts.
• Air filtration in production and packaging areas is provided by
filtration to at least 95 % ASHRAE (EU 9) .
• The air from the manufacturing areas of the facility is exhausted above
the building, through exhaust ducts equipped with 95 % ASHRAE (EU
9) filters at a minimum. For high potent drugs, HEPA filters are
required.
• There is no requirement for room cleanliness classification, based on
particle counts.
• With all doors closed, the rooms are balanced so as to create a relative
flow of air from the clean access corridors to the processing rooms.
Door opening shall be minimized at all times.
• Adequate quantities of air are supplied to and exhausted from the
rooms to provide an adequate number of air changes per hour. Dust
suction devices take part of the air balance in the room and should be
operated in conjunction with the HVAC system.
• Air inlets and outlets shall be located in a manner that provides the
adequate airflow pattern, taking into consideration the location of the
equipment and operators’ positioning. Air inlets are preferably located
in the ceiling, while air outlets are located in the walls, close to the
floor.
• Low humidity control is provided when processing humidity sensitive
materials.
• It shall be understood that automatic controls themselves are not
necessarily GMP significant. It is very important and recommended to
elaborate the GMP significant control parameters in the design stage.
• The monitoring of critical parameters shall be isolated from the control
system to avoid complexity.

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4.3.5.3 Monitoring Program

The routine monitoring program includes the following critical parameters,
that shall be controlled and continuously monitored, including alert and
action alarms (such as temperature, relative humidity) or periodically
monitored (such as air flow patterns, air changes and microbiological
contamination). Results shall be analyzed for trends.
• Temperature
• Relative humidity
• Airflow patterns
• Air change rates
• Microbiological contamination

For the principles of the microbiological monitoring program, see Section

10.5.1.3.

Table 4 - Testing Frequency

Temperature Continuous or at least three times a day
Relative humidity Continuous or at least three times a day
Air flow patterns Weekly
Air changes Quarterly
Microbiological contamination Weekly, preferably at the end of week as the worst
case

Table 5 – Environmental Conditions

Temperature Relative Air Changes Microbial Contamination Air Flow
(° C) Humidity (per hour) (CFU / plate) * Patterns
(%)
Storage NMT 25°C NC* NA NA NA

Production & 22±3°C NMT 70 * NLT 10 Alert 50 Positive from clean

Packaging Action 100 corridor to room
Laboratories 2±3°C NC * NLT 10 NA NA

NC = Not controlled, NA = Not applicable, NLT = Not less than, NMT = Not more than.
* Unless low humidity control is required and provided.

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4.4 Equipment

4.4.1 General
Equipment used in processing, packaging or holding of pharmaceutical products
shall be of appropriate design and size, made of adequate materials and properly
located and installed to facilitate the manufacturing and cleaning processes.

4.4.2 GMP Concerns When Purchasing New Processing Equipment

• Product contact surfaces shall not be reactive, additive, or absorptive. Surfaces
shall be hard and smooth, and shall not shed particles. Surfaces shall withstand
the repeated use of cleaning and sanitizing agents.
• The equipment shall be designed so as to prevent dead ends or spots, in which
products could accumulate and be hidden from the operator’s view.
• All parts of the equipment shall be easily dismantled to permit easy cleaning
and visual inspection.
• Valves shall be of a sanitary type.
• All connections to utilities shall be fitted with a back flow prevention valve
and with an atmospheric break to prevent back siphonage.
• Vessels and containers shall be drainable.
• Valves and instrumentation shall be installed flush with product contact
surfaces.
• Small parts, screws, and bearings, if unavoidable, shall be fixed in such a way
as to prevent their accidental fall into the product.
• Any substance required for operation, such as lubricants and coolants, shall
not come into contact with the product. The motor shall be located or designed
so as to prevent accidental dripping of these substances into the product.
• The motor and the electric and electronic parts shall be hermetically encased
to allow for easy cleaning and to prevent safety concerns during cleaning.

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4.5 Calibration

4.5.1 A calibration program shall be implemented to ensure that systems, equipment and
instruments operate within the required conditions .

4.5.2 A multi-disciplinary team representing Quality Assurance, Production and

Engineering shall determine the classification of instruments, as a significant
element to determine the frequency of calibration.

• Critical Instruments are any instrument :

- used to measure a critical process parameter
- from which the records are kept to demonstrate product quality
- whose malfunction may impact on product quality
- used for safety purposes
• Non-critical (or process control) instruments are any instrument:
- used to control or monitor the correct operation of a facility, system or
equipment
• Other (reference only) instruments, not requiring planned calibration but
calibrated on an “as necessary” basis:
- Utility system instruments
- Other non direct facility/systems/equipment related instruments

4.5.3 The calibration interval shall be defined according to the instrument criticality,
manufacturer’s recommendations and historical data. The initial calibration interval
shall usually be short and it shall be a subject to a formal revision process, based on
the instrument calibration history. Any increase in calibration interval shall be
supported by the history of the instrument performance and it shall be demonstrated
that the instrument would operate satisfactorily over the new interval. An increase
in the calibration interval may be considered after three successive calibration
checks without need for adjustments.

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4.5.4 Calibration failures of critical instruments shall be immediately reported to Quality

Assurance for evaluation of the impact of the failure on product quality.
4.5.5 Instruments shall be calibrated against master instruments, which shall be traceable
to national standard institutions.

The instrument calibration status shall be easily accessible and preferably marked
on the equipment, on which they are installed. Equipment, in which a critical
instrument is not within its calibration period, shall not be used. An equivalent,
calibrated instrument, which not an integral part of the equipment, may be used.

4.6 Validation

4.6.1 Commissioning and Installation

4.6.1.1 Commissioning (before and/or after installation) is the project phase that

includes mechanical completion, pre and post installation verification and

start up. It incorporates a systematic method of testing and documenting
facilities, systems and equipment at the conclusion of project construction
and prior to validation.

4.6.1.2 A well executed and documented commissioning plan may become an

integral part of the validation package. The minimum level of

documentation for facilities, systems and equipment shall include, the
following:
Š Design documents
Š Test procedures
Š Vendor/Contractor test and results

4.6.1.3 Before shipping, equipment may be commissioned at the supplier’s site

based on a protocol and a commissioning report shall be prepared at

completion including a list of findings that shall be corrected prior to
shipping (factory acceptance testing).

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4.6.1.4 Construction of a facility and installation of systems and equipment shall be

performed according to the supplier’s or contractor’s instructions.

Operators, technical/maintenance staff shall attend it as a part of the training
program.

4.6.1.5 Installation of new equipment and systems and facility construction shall be

done without disturbing the current production activity and without

violation of GMP.

4.6.2 Validation
4.6.2.1 Facilities, systems and equipment validation starts at the design phase and

includes commissioning, installation and operational qualifications. Written

operating instructions, maintenance and cleaning procedures are required as
part of the validation program. Validation is performed according to pre-
approved Installation and Operation Qualification (IQ, OQ) protocols.
Some systems and equipment also include a Performance Qualification
(PQ) protocol, to prove consistent process performance within pre-
determined acceptance criteria.

4.6.2.2 Acceptance criteria shall be established carefully, based upon those

parameters, which are important to the process, product or material,

allowing adequate tolerances .

4.6.2.3 A good approach brings the validation into the engineering projects early in

the preliminary design stage and conceptualization. The validation program

approach is outlined as follows:

Ö Phase 1 – Validation Master Plan (VMP).

The VMP outlines an overall validation plan and presents an organized
approach, as to responsibilities, the documentation required and the tests
to be performed.

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Ö Phase 2 – Validation Protocol

Describes how validation will be conducted and defines characteristics,
test parameters, test methods and acceptance criteria. The three levels of
qualifications are developed: IQ – that confirms that the validated object
was installed as specified, OQ – that demonstrates that the installed object
operates as specified and PQ – that demonstrates that the object will
perform the process consistently and reliably .

Ö Phase 3 – Protocol Execution

Follows approved protocols and data are collected .

Ö Phase 4 – Validation Report

Compiles collected data and concludes in a summary that the
accumulated data demonstrates a validated object.

Ö Phase 5 – Ongoing Evaluation and Change Control

Acknowledges the changes and modifications using the necessary
documentation and the continued validation program for the life cycle of
the equipment.

All the above mentioned documents must be approved at least by

Engineering/Maintenance, Production or R&D and QA.

4.7 Maintenance
4.7.1 Adequate maintenance shall be incorporated in the design of facility, systems and
equipment.

4.7.2 A preventive maintenance program is a key requirement and its careful

implementation shall be documented, reviewed from time to time and changes in
the program made when necessary.

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4.7.3 Manufacturer’s manuals and recommendations, historical operating data, general

engineering and maintenance data are the basis for the specific maintenance
procedures and their implementation frequency. Reliability and life expectancy of
various components must be challenged when preparing and implementing the
program.

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