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Pharmaceutical Utilities, current regulation,

qualification and validation

ETIF 2008Costa Salguero Centre - Buenos Aires - Argentina

24 October 2008

Giovanni Bini

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Contents

Pharmaceutical Utility Systems

Systems Design & Validation Approach

A validation approach example: WFI distribution system

Commissioning

Normative ReferencesThe design phases

• User Requirements Specifications• Functional Specifications• Design Specifications

The Validation phases• Design Qualification

The Validation phases• Installation Qualification• Operational Qualification• Performance Qualification

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Pharmaceutical utility systems

Each pharmaceutical (but also cosmetics, food, chemical…) industry’s manufacturing process uses several support system with different functions and

generated and distributed with centralized installations.

These systems are not necessarily designed and customized for users of a single production facility, but

often serve an entire factory or part of it.

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The most common systems of this type are:

•• Process waters Process waters (different types)•• Cooling and/or heating fluids Cooling and/or heating fluids (steam, water, brain,

diathermic oil, etc) •• Air conditioning Air conditioning (HVAC systems)•• Compressed air, nitrogenCompressed air, nitrogen•• Burning gasBurning gas•• Process gas Process gas (CO2 , O2 , etc)•• Drinking and sanitary waterDrinking and sanitary water•• FireFire--fighting waterfighting water•• VacuumVacuum•• Various kinds of waste system Various kinds of waste system (rainwater, medical,

process, biological, gas, etc.) •• Electric powerElectric power


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A good working of these systems ensures efficiency of production.

For example, the sudden lack of steam might impair a heating phase (e.g. during a synthesis reaction) or a sterilization cycle, with the risk of compromising an entire batch of production. The lack of vacuum

might block a filtering or drying process, causing damage to the product.

An accurate preventive maintenance program of the systems can limit such incidents and subsequent blocks of production.


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The production support systems used in pharmaceutical industry can be classified in three categories as follow:

•• process systems process systems (direct impact system)

•• process support systems process support systems (indirect impact system)

•• utility systems utility systems (non-impact systems)


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Process systems (direct impact systems)

They are:

• in direct contact with the product;

• in contact with those materials which will later be transformed in the product or will be in direct

contact with it.

For example, process water (water for injections, purified or drinking water) are generally considered as direct process systems.


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They are always considered critical because they are actually or potentially in direct or indirect contact with the product.

They must be designed and constructed considering the needs of product quality and to prevent any contamination to the product

itself. Incorrect design and/or construction methods may leave residues on

the inner surface of equipments or pipes that can cause contamination of the distributed fluid and, consequently, of the

product. For these reasons, it is often important to have a high degree of

surface finishing, or specific methods of construction (e.g. welding), or cleaning and keeping systems that can provide the necessary level

of protection against contamination.



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From a GMP point of view, support systems that meet the definition of " process systems ", should be considered as real raw materials.

Due to the fact that process systems can directly, indirectly or potential affect product quality, the same degree of control of the production process should be applied to them, and they must be

qualified according to the classic approach of validation.

It is also important to check the qualitative aspects of the material that comes to points of use (usually consisting of a fluid), since any

chemical or microbiological contaminants impurities would be found in final or intermediate products, and compromise quality.



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Process support systems (indirect impact systems)

They directly support process operations, but have no contact with the product or with materials that will be

transformed into product.Some examples of support systems for the process: cooling and

heating fluids that exchange heat with process materials through a surface (heat exchange jacket applied to reactors, tanks, dryers, etc...

shell and tube, double pipe, plate exchangers, etc…)

The solutions used for equipment and/or machine washing (CIP systems - Cleaning in Place or manual systems for washing) are

generally considered process support systems, except those used for the final rinsing that are considered as process fluids.


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The process support systems are not generally considered critical

In these systems, in general, the qualitative aspects of the fluid have no relevance. Instead the physical features available at point of use (temperature, pressure, flow, etc..), and availability for the needs of process in contemporary condition of use with other points of use

have more relevance.

From a GMP point of view, system availability to users has relevance, while the qualification of plant and functional aspects of the system

follow the Good Engineering Practices (GEP), which are based mainly on the proper design and a comprehensive "commissioning" of the system (drawings "as built", tracking changes, testing, SOPs, etc.).

Process support systems (indirect impact systems)


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• They are not in contact with the product or material that will then be transformed into product;

• They are not customized systems to specific users but distributed with general networks serving all the

users of the factory;

• They deal with side effects of an industrial production such as waste disposal.

Examples of service systems are the systems of drinking water, sanitary water, electricity.

Utility systems (non-impact systems)


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Typically, such systems did not impact on the product quality and, therefore, are never considered critical.

In this case also, the qualification of the plant and operating systems follows the good engineering practices

(GEP).

Electricity can instead have a critical role (e.g., Loss of data or interruption of production processes).

In these cases the supply to its customers critical points is ensured by appropriate systems (automatic back-up

generators, un-interruptible power systems), that are able to overcome possible discontinuity of supply from the

distribution network.

Utility systems (non-impact systems)


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EU GMP volume 4Annex 15 - “Qualification and Validation”(2001)

ISPE Baseline Engineering GuidesVol. 5 -“Qualification and Validation”(2001)

PIC/SPI 006/2 - “Recommendations on VMP, IQ and OQ, non sterile

process validation, cleaning validation”(2004)

FDA“General Principles of Process Validation”(1987)

Systems Design & Validation ApproachNormative References

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Qualification and Validation of the manufacturing and process systems, facility and equipment is intended as the documented verification that they, as installed, comply with the approved design, operate within the approved functional specification and are consistently able to perform the scopes they has been intended for.

Consequent by above definition, GxP Critical System Qualification and Validation Execution could be performed only if correct and exhaustive Design has been done, aimed to define documented and approved intended use, scope, operative range, not only for the system itself but also for system’s component, building characteristic and installation.


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THE DESIGN OF THE MANUFACTURING SYSTEMS / WATER DISTRIBUTION FOR PHARMACEUTICAL USE SHOULD BE STRUCTURED UPON THE GOOD

ENGINEERING PRACTICES (GEP), UPON THE THREE PHASES:

User RequirementsSpecifications

FunctionalSpecifications

DesignSpecifications

The Design Phases

Documents describing the building details and the specs of installation of the system, on the basis of which the system itself will be built

Document that defines a system and/or its components in terms of functions that must be performed and or services that must be attached to the system itself to satisfy the URS

Document that defines in a clear, precise and concise way what the user wants the system to do: conditions, starting specs, functions that must be performed; specs as outcomes; environmental conditions in which the system operates and eventual constraints


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Planning for Validation

2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents.

3. The VMP should be a summary document which is brief, concise and clear.

4. The VMP should contain data on at least the following:(a) validation policy;(b) organisational structure of validation activities;(c) summary of facilities, systems, equipment and processes to be

validated;(d) documentation format: the format to be used for protocols and

reports;(e) planning and scheduling;(f) change control;(g) reference to existing documents.

(EU GMP - Annex 15 – Qualification and Validation)


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DESIGN QUALIFICATION = DQ

INSTALLATION QUALIFICATION = IQ

OPERATIONAL QUALIFICATION = OQ

PERFORMANCE QUALIFICATION = PQ


The Validation Phases


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PerformanceQualification

OperationalQualification

InstallationQualification

System build& Commissioning

DesignQualification

Design phasesQualification

phases

The Validation Phases


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A validation approach example: Water for Injection distribution system

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USP 31Monograph <1231> - “Water for Pharmaceutical Purposes” (2008)

FDA“Guide to Inspections of High Purity Water Systems” (1993)

ISPE Baseline Engineering GuidesVol. 4 & APPENDIX -“Water and Steam Systems”(2001)

ISPE Best Practice Guides“Commissioning and Qualification of Pharmaceutical Water and Steam

Systems” (2007)

Normative References

Water for Injection distribution system Validation

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The purification processes (pre treatments and final purification) must produce water of the required quality

&The storage system and the distribution of the water for pharmaceutical

use must not alter the quality of the water in the points of use.

The Design PhasesUser Requirements Specifications

WATER FOR PHARMACEUTICAL USE MUST NOT INTRODUCE IN THE PRODUCTS ESTRANEOUS ELEMENTS THAT COULD CONTAMINATE IT

OR REACT WITH IT


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• Distribution system in loop• Limitations of the dead legs• Minimum speed of the water • Materials in contact with water• Sanitization system• Surface finishing• Typology of the equipment and accessories of piping• Junction typology • Welds • Sampling points• Drainage

Flow-rate, quantity and frequency of the samples at points of use Location of the points of useTemperature of use in the points of useGMP requirements recommended by normative or guidelines:

The Design PhasesUser Requirements Specifications


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Circulation flow and maximum simultaneously samplings Storage volume P&I scheme of the system (equipment, instruments, regulation loop, control system)Dimensioning of the main equipment Piping trackSpecs of the materialsFunctional specs of the equipment and of the instrumentsPiping specsFunctional specs of the control system (sequences, operator interface, printings, videos, access, security, audit-trail, etc..).Application of the GMP requirements from the norms and the guide-lines.

The Design PhasesFunctional Specifications


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Preliminary P&ID

The Design PhasesFunctional Specifications


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Building drawings of the main equipment Selection of the equipment and standard instruments Piping dimensioningBuilding piping sketches (welds position, sloops)P&I scheme for buildingImplementation and customization of the softwareEtc…

The Design PhasesDesign Specifications


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Final P&ID



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Final P&ID



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Isometric Sketch



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Isometric sketch



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DESIGN QUALIFICATION = DQDESIGN QUALIFICATION = DQ








DesignQualification

The Validation PhasesDesign Specifications


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European GMP – ANNEX 15 ed.June2001

“The first element of the validation of new facilities, systems or equipment could be design qualification (DQ)”

(punto 9)

“The compliance of the design with GMP should be demonstrated and documented”

(punto 10)



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EXAMPLE

URS Level Requirements for drainage

FS Level Slopes towards the lowest points

DS Level Sketch Test



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Isometric sketch for the slope verification



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Once the design has been qualified and approved, it is being carried out to its completion the phase of commissioning starts:

Activities (verifications, tests, set point operations, calibrations, startups) that have the aim of put the system under conditions to operate in a conform way to its scopes.

Most of these activities can be “used” for the following phases of qualification, but they must be performed and documented according to the cGMPs.

Particularly in the phases of startup, the acceptance of the (FAT, SAT) can allow good synergies to be used in the qualification phases.

The Commissioning Phase


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Commissioning activities• Verification of the system conformity upon the specs and the purchase order • Supplier documentation collection, control and adequacy verification• FAT and SAT non conformities resolution verification• As-Built drawings (P&ID, electrical schemes, isometric sketches, etc...) on

field verification • Verification of the system components upon the cGMP requirements• Initial calibration of the critical instrumentation • Operators’ training• Operational tests of the components (engines, sensors, controllers)• Functional test of all the operative range of the system (reliability and

stability of the system functions)• Set-ups, PID control algorithms, thresholds, etc. Optimization• Design documentation updating, changes documenting • Alarms and interlocks tests• Control system I/O test• Operational sequences test• Etc….



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The importance of the “as built” drawings

In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated?How can a quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.

Rif.: FDA Guide to Inspections of High Purity Water Systems (1993)



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InstallationQualification


INSTALLATION QUALIFICATION = IQINSTALLATION QUALIFICATION = IQ




The Validation PhasesInstallation Qualification


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Compliance with installation and startup procedures.Supplier manuals.Certifications.Drawings «as built»: P&ID – electric schemes – isometric sketch– etc….Tagging of all the system components, of the instruments and of the support utilities. Availability of the samples pointIdentification of the critical instrument and the formalization of a periodic calibration control program.Standard Operating Procedures (SOP) for the use of the system, for its cleaning, its maintenance, the calibration of the critical instruments, etc., (at least in draft).List of the critical spare parts.Significant characteristics of the system, and of its significant components with the recording of the principal data (manufacturer, type, model, serial #).

Verifications



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Tracks and SlopesMaterials in contact with waterWeldsPassivationBoroscopic inspections

The documentation collected in this phase is inserted in the report of Installation Qualification:

Building sketches as-built Certifications of the materials that come in contact with water “Welding book”, welding procedures, welding samples, identification of the used orbital weldings.Procedure and certificate of passivationDocumentation of the boroscopic inspections

Tests to be performed during system installation



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OPERATIONAL QUALIFICATION = OQOPERATIONAL QUALIFICATION = OQ




OperationalQualification

The Validation PhasesOperational Qualification


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To guarantee that the system is adequate to serve different user points, satisfying the needs of the process from the

quantity point of view (Flow-rate, temperature, pressure, etc…) and from the quality point of view (chemical- physical

and microbial characteristics).

Objective



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Approved SOPs must be available (at least in draft: following the results of the CQ tests it is possible that is evidenced the need to include adequate corrections applied to the SOPs following the workflow for the approval).

Utilities (clean steam, industrial steam, cooling water, compressed air, electric energy, etc...) must be completely operative and able to maintain the established supplying specs (temperature, pressure,quantity, electric power, etc.).

Critical Instrument for the control of the system and that used for the OQ tests must be calibrated in compliance to the procedures approved and referable to the Metrology recognized Institution.

Analytical Methods as a support for the tests as in the OQ protocol must be available and duly qualified.

Verification and tests



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Control system verification tests :• I/O Signals• Alarms• Operation sequences• Interlocks• Power fail and system re-start up• Passwords• Functionality of the operator interface• Printouts and video images• Audit trail• Functioning of the loops/regulation algorithms, etc.

Verification and tests

Flow rate at the points of use.Water speed in the loop (choosing the worst case, e.g. in the return pipe under conditions of maximum sampling)

Temperature in the distribution loop and at points of use.

Sterilization cycle verification and temperature mapping.



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Many tests included in the OQ protocol can be extracted, if executed and documented in the right way, from the tests and the verifications of SAT. Particularly:

Test of the control system

Test of the flow-rate and of the speed velocity

Loop and points of use temperatures during operation.

Sanitization cycle verification and temperature mapping.

Tests to be performed during the SAT



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WFI – Temperature mapping during Steam sterilization test:

• In case we want to perform the test in a less invasive way we can insert probes externally to the pipes.

• It exists a thermo gradient between the internal part and the exterior of the pipe responsible of a heat flow exchange: the use of an appropriate external insulation system can reduce the temperature losses on the external side but cannot eliminate it.Steam flow

Tri-clamp connection o-ring

Thermocouple

Coating of insulating material



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PERFORMANCE QUALIFICATION = PQPERFORMANCE QUALIFICATION = PQ



PerformanceQualification

The Validation PhasesPerformance Qualification


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To verify and give documental evidence that the system can supply water to the user points, in a continuous and reproducible way, under the working conditions detailed in the operating procedures, at the operation temperature and respondent to the qualitative specs (chemical – physical and microbial) already set, maintaining the values of the critical parameters of functioning of the system within the pre established values. The tests must include all the cases of variability of the factors that can have a potential influence on the water quality (i.e. those induced by seasonal cycles) and/or taking into consideration situations of worst-case for the performance of challenge tests.

Objective



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Systems of critical utilities that have been qualified.SOPs for the operation and the maintenance of the system approved in a final form.Critical Instruments, for the control of the system and that used for the PQ test, calibrated in accordance to the procedures approved and referable to a metrology recognized institution (NAT).Analytical Methods for the tests included in the PQ protocol qualified

Verifications and test



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Test of maximum simultaneously sampling.

Verification test of microbial quality water maintenance Test (optional or to be associated to other quality tests).

Test to verify the efficacy of the sanitization system (with thebiological indicators or other challenge systems – optional).

Water quality at the sampling points.

Verifications and test



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WFI - Steam sterilization test:

In order to create a “worst case” challenge to verify the effectiveness of the sanitization cycle, spore strips, normally coupled in thermocouples, are sometimes used. This practice is not recommended, because of the contamination risk for the entire loop in case of a strip rupture: Steam flow

Spore stripPergamine coating

Scotch tape

tri-clampjoint o-ring

Thermocouple

"Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function."

FDA - Guide to Inspections of High Purity Water Systems (1993)



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The PQ quality testing plan for a WFI System should provide three successive phases, as recommended in the FDA Guide to Inspections of High Purity Water Systems, (1993).

First phase of PQ quality testing“Sampling should be daily after each step in the purification process

and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, then the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOPs for operation of the water system.”

The objective is to demonstrate that the system is able to supply to the users water meeting the appropriate specifications



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Performance Qualification recommended Program for a WFI production and distribution system

Second phase of PQ quality testingThe second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs.The sampling is performed as in the initial phase and for the same time period. At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.

FDA Guide to Inspections of High Purity Water Systems, 1993



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Third phase of PQ (Monitoring phase)The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater that could affect the operation and ultimately the water quality will be picked up during this phase of the validation. Sampling is performed according to routine procedures and frequencies. For Water for Injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly.The validation of the water system is completed when the firm has a full years worth of data.


Performance Qualification recommended Program for a WFI production and distribution system



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Performance Qualification for a production and distribution systemRecommended Procedure for a WFI system

Validation dataWhile the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system.

• First, there must be data to support the SOPs. • Second, there must be data demonstrating that the SOPs are valid and

that the system is capable of consistently producing water that meets the desired specifications.

• Finally, there must be data to demonstrate that seasonal variations in the feedwater do not adversely affect the operation of the system or the water quality.




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Sampling rules1 Samples should be taken directly from the point of use.2 From the taps where the sampling is being performed (or from a dedicated port

placed upstream or downstream of the point of use).3 If a single point is being used for multiple applications, i.e. on the transfer

piping the sampling must be performed at the end of the pipe. 4 If the pipes are sanitized once a day (or after a pre-determined time delay) the

sampling must be performed before the pipes sanitization cycle.5 If the SOP calls for the line to be flushed before use of the water from that

point, then the sample is taken after the flush.6 Record the hour the sampling has been performed.7 Suggestion to sample the same point at different times.

“The Worst Case criterion must always be respected”

Performance Qualification for a production and distribution system



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Thank you for your kind attention

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