A Pharma Guide to Planning and Constructing Cleanrooms...A Pharma Guide to Planning and Constructing...

A Pharma Guide to Planning and Constructing Cleanrooms

GMP Series

Excerpt from the GMP Compliance Adviser

Harald Flechl

Harald Flechl

A Pharma Guide to Planning and Constructing Cleanrooms

Cleanroom_construction_components.book Seite 1

Contents

A Pharma Guide to Planning and Constructing Cleanrooms © GMP-Verlag Peither AG 1

Contents

1 Cleanroom construction components 2

1.1 Introduction 2

1.2 Requirements originating from laws, rules and guidelines 3

1.3 Selection and procurement 5

1.4 New technologies for project planning 11

1.5 Wall and ceiling systems 12

1.6 Windows and doors 22

1.7 Floor systems 30

1.8 Application areas of construction components for different cleanroom classes 44

1.9 Example of a risk assessment for surfaces 47

Contributors 50

Index 51


Cleanroom construction components


1 Cleanroom construction componentsHarald Flechl

1.1 Introduction

Depending on the cleanroom class and the manufacturing process, special requirements apply notonly to the environmental conditions for the manufacture of pharmaceutical products, but also tothe construction components of the production facilities.

The pharmaceutical industry is subject to strict regulation and is considered to be very averse toinnovation. Indeed, authorities and auditors often misinterpret specifications from guidelines asbinding, which are merely recommendations. Benchmarking with comparable projects and the shar-ing of experience with competitors and related industries are therefore very important and havemade many innovations in the pharmaceutical industry possible.

This chapter is intended to provide support in the planning of new construction or remodellingprojects in the pharmaceutical industry.

First, the basics and requirements for the planning of a construction project are presented. In the fol-lowing chapters you will learn• Which specifications need to be reflected when planning a construction project (chapter 1.2 Requi-

rements originating from laws, rules and guidelines)• How the process progresses from concept to completed room (chapter 1.3 Selection and procure-

ment)• How you can optimise the planning process by using new technology (chapter 1.4 New technolo-

gies for project planning)

In the subsequent chapters, the individual components are presented. What is the current state ofthe art? What design variants are there? What details have to be taken into account in order for theresult to be GMP compliant? In these chapters you will also find selection checklists as well as numer-ous illustrations and schematic drawings.• chapter 1.5 Wall and ceiling systems• chapter 1.6 Windows and doors• chapter 1.7 Floor systems

Given the large number of possible design variants and materials, the question arises as to whichcomponent and which design are suitable for which purpose. A tabular overview for the cleanroomclasses A-F can be found in• chapter 1.8 Application areas of construction components for different cleanroom classes

Here you will find answers to the following questions:• Which legal and regulatory requirements must be met when selecting construction

components?• How can different requirements and recommendations be met economically?• What method can be used to achieve a GMP compliant and economical level of construction

quality?• Which systems are GMP compliant?• What proven construction methods are there for the renovation and new construction of

different cleanroom areas?• What details should be kept in mind when selecting components depending on the purpose of

use?• How can one assess the risk of a component’s surface?




Since this classification is based on the interior room surfaces, a risk assessment of the surfaces canprovide an important basis for decision-making. You will find an explanation of how this can be donein• chapter 1.9 Example of a risk assessment for surfaces

1.2 Requirements originating from laws, rules and guidelines

1.2.1 Eurocode Standards

The requirements for the construction industry are regulated by the binding Eurocode standards.The Eurocodes are a set of European standards for the construction industry. There are currently 10Eurocodes (EC 0 to EC 9 in standards EN 1990 to EN 1999, see figure 1). These are subdivided into 58sub-norms with supplementary national annexes covering all main fields of construction.

The Eurocodes are used to implement directives of the European Commission. These guidelinesmust be transposed into national law by corresponding legislation. In Germany, the constructionregulation for submitted building projects has been implemented since July 1, 2012 and the Euroco-des are therefore applicable law.

1.2.2 Agency requirements

In addition to the GMP requirements, it is also mandatory to meet and comply with official specifica-tions and requirements. These requirements can vary greatly from region to region and, in additionto the financial aspects (e.g. levies, taxes), constitute further decision-making criteria for a newlyplanned location or the renovation of an existing building. The requirements of change manage-ment must also be complied with.

Examples for mandatory agency requirements (laws and regulations) include:• Federal and state construction code• Construction laws, zoning of property• Worker protection – provision of equal access for handicapped persons

Figure 1 Eurocode groups (Beuth Verlag, 10787 Berlin, www.beuth.de)

Eurocode 3Steel structures

Eurocode 4Composite structures

Eurocode 2Concrete structures

Eurocode 5Timber

structures

Eurocode 9Aluminium structures

Eurocode 6Masonry

structures

Eurocode 8Earthquake resistence

Eurocode 0Basis of structural design

Eurocode 1Actions on structures

Eurocode 7Geotechnical design




• Fire protection• Structural stability (earthquake zones)• Commercial law• Environmental protection – emissions and immisions• Non-slip floor surfaces• Noise emissions to surrounding residences• Requirements placed by trade supervisory board (maximum noise level at workplaces, ability to

view the outdoors from the workplace etc.)• and further local authority requirements.

Sound absorption values for ceilings, walls and floors as well as footfall sound insulation are usuallynot specified by the authorities for industrial buildings.

1.2.3 Standards and guidelines

Recommendations for implementation are given in the various pharmaceutical guidelines and ISOas well as EU and country-specific standards (DIN, OENORM, etc.) to be able to comply with legalrequirements.

While the standard ISO 14644-4 corresponding to VDI 2083 Part 4.1 defines only general structuraland user-related requirements, the ISPE guideline (ISPE Baseline Guide Vol. 3 Sterile ManufacturingFacilities) makes specific recommendations for the selection of materials for surfaces and surfacecoverings.

In addition, there are a considerable number of technical rules for the construction and testing offloors, i.e. national, EN and EN-ISO standards. The construction of cleanroom floors can therefore beeffected by considerably more technical regulations than the construction of cleanroom ceiling andwall systems.

A step-by-step and systematic procedure for GMP-compliant building expansion is described inVDI 2083 Part 4.1. The topics of risk assessment and quality assurance – basic elements in phar-maceutical plant construction – are also dealt with in detail in this guideline.

1.2.4 GMP requirements

With respect to the requirements for pharmaceutical production premises, the GMP regulations con-tain only general statements such as:• Appropriate for the intended use• Adequate space for production including materials, equipment and personnel• Design according to the current state-of-the-art• Properly sealed components (walls, floors, suspended ceiling)• No uncontrolled dead spaces or links to the surrounding environment.

Premises for sterile production should be smooth, leak-proof and free of cracks according to the phar-maceutical guidelines (e.g. Annex 1 of the EU GMP Guidelines and other GMP regulations). The releaseor accumulation of particles and microorganisms or emissions of molecular gases should be avoided.

The GMP regulations also contain the following requirements for the surface quality of the compo-nents:• Smooth, sealed, leak-free surfaces without cracks or non-accessible seals• No emission or collection of particles possible• No breeding ground for microorganisms• Ease of cleaning and avoidance of hard-to-reach surfaces• Proven compatibility for intended cleaning agents and disinfectant as well as the frequency of use• Access for maintenance from outside the cleanroom if possible




The same shall apply accordingly to the routing of pipes, other installations and fixtures. An exampleof poor accessibility for cleaning can be seen in figure 2. Unfortunately, this type of installation is verycommon – it would be better to clad the pipe all the way up to the ceiling or to increase the distanceto the ceiling during installation.

1.2.5 Other aspects

In the case of some pharmaceutical manufacturers, special requirements of the insurance company(corporate insurers) must also be reflected. Compliance with these requirements influences the levelof insurance premiums and coverage.

Unfortunately, there is no patent recipe for a generally suitable and economical solution. Require-ments, benefits and necessary investment must always be considered in context in order to find theoptimal solution with the most favourable life cycle costs for the planned demand. Clarifying thefinancing for a planned usage period (e.g. limited period of production of max. 5 years) can also leadto a leasing alternative with fixed costs for production, qualification, operation and maintenance.

1.3 Selection and procurement

1.3.1 Which factors influence component selection?

In selecting the construction components, important factors to consider are• the process and product-specific requirements to be derived from the manufacturing processes,• the resulting specified cleanroom classes,• the desired flexibility (single or multi-purpose) and• the intended detergents and disinfectants.

National and international guidelines also require risk assessments when designing plants and whendetermining the scope of qualification/validation.

This gives rise to special hygienic and cleanroom requirements for components. Different require-ments also result from the intended type of usage. Administration, research and laboratory buildingshave different requirements than production rooms. The requirements for production areas andclean rooms used for pharmaceutical purposes have a higher standard than other buildings, even ifthese components are not in direct contact with pharmaceutical products. An example of a risk-based assessment of surfaces in connection with their proximity to the product and cleanability isdiscussed in chapter 1.9 Example of a risk assessment for surfaces.

Figure 2 Piping installation – non-accessible areas for cleaning.




1.3.2 How do the requirements put on rooms for pharmaceutical use differ from the requirements put on other building types?

• Higher sealing requirements for external façades. A maximum specific façade leakage of< 0.3 m³ x h-1 × m-2 at a static pressure of 500 Pa to minimize the rate of incursion of particles fromoutside1

• Higher seal effectiveness requirements for the surrounding surfaces of a cleanroom (increased sealeffectiveness can also lead to problems regarding control of room pressures)

• Smooth surfaces free of pores, free of cracks and uncontrolled dead spaces which are not easy toaccess for cleaning

• Not susceptible to accumulate or release particles or release gasses from component materials(“molecular contamination”)

• No materials which could serve as breeding grounds for microorganisms• Resistant to intended detergents and disinfectants and cleaning procedures• In certain cases, properties impacting electrostatic charges are a criterion (e.g. when processing

powders, during media transfer into plastic tubes)• Other installations (pipes, air ducts, electrical installations) should be installed in a manner condu-

cive to cleaning – cladding all the way up to ceiling or assurance of a minimum distance accordingto the cleaning procedures (see figure 2)

• Simple and properly sealed incorporation of various installations such as airflow vents (inlet, ex-haust, cross flows), lighting installations, smoke detectors, sprinklers, etc.

Special operational requirements can also include measures for ergonomic workstation design thatis well accepted by the operating personnel (e.g. colour schemes for surfaces, etc.)

The need to provide greater heights and thus increased space for the room-air installations abovethe cleanroom ceiling and their accessibility for maintenance is also an essential factor in the shellconstruction.

In the following chapters, the design options for pharmaceutical cleanroom construction of GMPclasses A–D are described. The requirements for non-sterile production are not as high. Solutions fornon-sterile production and also temperature-controlled areas (cooling rooms, incubation rooms,etc.) are not explicitly dealt with here, but can be applied analogously.

1.3.3 Good Engineering Practice (GEP) for procurement

Beginning from the definition of the User Requirements Specification (URS) the planning phase issubdivided into four stages:• Pre-planning• Concept planning• Fine planning• Execution planning

The implementation phase includes three stages:• Execution/construction• Commissioning, training• Qualification

This scheme is based on established Good Engineering Practice (GEP) principles. It should be notedthat pharmaceutical authorities also recommend GEP as a methodology for the design of phar-maceutical plants.

1. From Report No. 6, Particle transport through leaking façades (Partikeltransport durch undichte Fas-saden), Dohm Pharmaceutical Engineering, Dr.-Ing. Wolf Ziemer, DI(FH) Mike Urack, May 2009,www.dphe.de




The essential elements of GEP in the conception, planning and construction of pharmaceutical pro-duction facilities are summarized below:• Observance of local construction laws and other relevant regulations• Knowledge of pharmaceutical regulations• Knowledge of relevant regulations and pharmaceutical guidelines• Observance of the principles of cleanroom technology according to the current state of the art and

science2

• The development and evaluation or weighting of all requirements together with the user based onthe requirements of the manufacturing process

• The consideration of process, material and personnel flows in order to eliminate or at least reducepossible contamination risks

• The application of value analyses and risk assessments in the selection of options.

All these requirements are handled step-by-step and iteratively (see figure 3) and are included in theURS. They form the basis for further qualification steps as a precondition for pharmaceutical use.Annex 15 of the EU GMP Guidelines also describes, among other things, the requirements for quali-fication of plants and equipment.

In practice, it has proved successful to provide a room book as an appendix to the URS for clean-room construction and also to use it for checking the FDS (see chapter 3.A.5.2 Room book). In the con-text of qualification, it can also be used as a reference document for the verification of the individualqualification steps.

The Functional Design Specification (FDS) provided by the supplier specifies how the URS will beimplemented. The FDS is then checked for plausibility and fulfilment of all the requirements listed inthe URS and adapted, if necessary, or rejected (see figure 3 and figure 4).

The terms "URS" and "FDS" are less common for cleanroom construction and utilities engineering(electrical, ventilation, air conditioning, compressed air, etc.). The planner usually creates a list ofspecifications with functional descriptions, quantities and services on the basis of the specificationsin the URS. This performance specification list is regarded as equivalent to an FDS and does not haveto be "translated" into a new document.

Even if the procedure shown in figure 3, especially in the initial phase with the loop for adaptation ofthe concept (1) – (2), looks very complex and time-consuming, economic solutions are possible.

2. Standards and other guidelines are to be considered only as recommendations and do not alwaysrepresent the current state of the art.




1.3.4 Qualification

A completed qualification of the structural equipment/components provides conclusive confirma-tion of their suitability for pharmaceutical production. Up to this step, changes are documented witha technical project change protocol.

If adjustments or changes are required after qualification in preparation for process validation,these are processed and documented within the framework of internal quality change management(change control) (see figure 3). In this case, the changes are to be assessed and evaluated under theaspect of possible influences on the process and the product quality.

Figure 3 The path from concept to qualified system

Checkversus URS

Supplier selection A, B, .., N

Concept target scope

Eng

inee

rin

g C

han

ge

Con

trol

LawsGMP

Define requirements for documentation

Design Qualification

(DQ)

Requirements in URS

FDS

Award contract

3

Risk analysis

Check documents

Installation Qualification

(IQ)

Check documents

Visual check, IQ tests

Calibration of critical instruments

Functional/Operational Qualification

(OQ)

Equipment functionality

Alarm inducement

Functionality of integrated systems

(e.g. controls)

Performance Qualification

(PQ)Co-ordinated operation of integrated systems

Performance test versus URS

Definition of monitoring points Plant or system ready

for process validation

Production runs,corrective and

preventive maintenance

Quality Change Control

1

Assess and test

ideas

2adapt




1.3.5 Economic and financial aspects

The list of specifications is provided by potential suppliers including prices. This makes it possible tomake direct prices comparisons of the tendered services according to the same technical specificati-ons. The potential suppliers have the opportunity to recommend alternatives which can be com-pared according to quantitative and qualitative criteria and the expected cost-benefit ratio over theentire lifecycle (procurement, maintenance, operating costs). An example of an internal assessmentscheme is provided in figure 4.

The planned service life and the cost-effectiveness of the investment and maintenance expenditureare to be optimised taken together as the life cycle costs (LCC). In the TCO analysis (Total Cost of Own-ership – figure 5), the costs from the planning phase, construction and usage as well as demolitionand disposals are taken into account. As can be seen from figure 5, the operating and usage costs ofthe project far exceed the construction costs. It therefore makes sense to take operating costs intoaccount and optimise them already at the design stage.

Figure 4 Example of a procedure for the assessment of a Functional Design Specification

Check that Functional Design Specification meets intent of User Requirement

Specification

Value analysisreflecting input

from:- Experts- Purchasing- Users- Maintenance- Cleaning

amount(quantitative)

technically suitable

(qualitative)

comparability of alternatives

references(supplier

suitability)

reje

ct

Award of contract and definition of guaranteed parameters, delivery dates and

responsibilities




In the planning phase (concept, design, engineering), the potential for influencing costs is particu-larly high. In addition, modifications in this phase incur only low costs and effort. These increase overtime with the level of planning detail and once construction has been initiated. If changes are stillrequired after completion and commissioning, this is always the most costly option (figure 6).

Figure 5 Total cost of ownership assessment

Figure 6 Ability to influence investment costs over the course of a project (source: Dr. Jan O. Fischer, Gesellschaft für kostenorientierte Projektentwicklung (Society for cost-oriented project management))

Ability to influence

Real estate costs

Total building cost (after 40 years)

Planning and construction costs

Planning Construction Use Demo-lition

Total cost of ownership assessment (Lifecycle)

Development of




1.4 New technologies for project planning

A cost-optimized approach to project planning and execution, including the use of BIM (BuildingInformation Modelling), will be used increasingly in the future. If this technology is applied correctlyand over the entire project sequence, it makes it possible to optimise the planning, execution andusage of buildings, furnishings and installations using digitally prepared product data and software.

In Great Britain, BIM is already standard for public tenders. Major projects in particular ran moresmoothly there than other known projects and planned schedule and cost targets were met. Further-more, BIM is to be made mandatory in Germany from 2020 as a planning basis for public tenders.

BIM facilitates planning through object-oriented, intelligent digital building models by creating acomprehensive process with a uniform database. Instead of many individual drawings, the informa-tion from diverse specialist areas is combined in a common interdisciplinary data model.

Having an influence on costs is therefore also possible earlier and at lower cost than in conventionalpaper-based planning with the associated complex communication channels (figure 7).

Since all project participants access the same data in "real time", changes are immediately visibleto all without delay. If, for example, the walls and number of doors are changed, the defined parts list,the room areas and thus also the costs change in parallel.

In addition to its geometry, an element's technical information is also contained in the buildingmodel, e.g. surfaces of wall elements (see figure 8), cleaning specifications for surfaces, etc. This pro-vides the relevant data for further planning, risk assessment (chapter 1.9 Example of a risk assessmentfor surfaces), construction, documentation and subsequent operation of the building.

Figure 7 Influence of BIM on cost development




Based on this building model, both the construction process and subsequent operation in the build-ing can be simulated. Potential errors during the construction phase, such as collision problemsbetween the various structures, can be avoided in advance. The increased cost, schedule and plan-ning security thus achieved ensures more efficient planning processes and risk containment.

Room and process planning with VR (virtual reality) are also being implemented already. Comput-ers are used to realistically illustrate the handling of simulated systems, machines and work equip-ment. The working environment appears in its natural size and allows weak points to be identified inan early stage and planning to be adjusted.

1.5 Wall and ceiling systems

What is the current state of the art for ceiling and wall systems, i.e. what can the user expect fromcompetent and experienced suppliers today? What differences between the selected suppliersshould be considered when evaluating offers and options? The following checklist is intended toprovide assistance in this respect.

Figure 8 Example of a BIM model for wall elements

Checklist for wall and ceiling systems Meets expectations?

Assessment criteria yes no n.a.

Well established and accepted design

Seal quality can be tested if necessary

Defined materials of construction according to agency or internal cus-tomer specification

Appropriate fire resistance grade for materials used in fire barriers and load bearing structures

Figure 9 Checklist for wall and ceiling systems

PanelsCharacteristic Floor Surface area (m²)

System element Metal panel 1st story 140.33

System element Metal panel E130 1st story 356.65

System element Glass wall element 1st story 479.26

System element Glass wall element E130 1st story 879.27

System element Metal panel 2nd story 136.02

System element Metal panel E130 2nd story 76.96

System element Glass wall element 2nd story 56.02

System element Glass wall element E130 2nd story 102.06

System element Metal panel basement 428.81

System element Glass wall element basement 277.02

Total 2,932.40




Size and arrangement of suspended ceiling elements: perimeter profiles, locking profiles, (sandwich) panels; ease of modifica-tion, ability to augment and dismantle

Well-designed wall-to-wall, wall-to-floor and wall-to-ceiling interfaces including tolerances and elevation adjustment systems

If connections with radius coves are desired, pre-installed corner cove profiles are superior to subsequently installed cove profiles for hygienic reasons (uncontrolled dead space behind the profile).The cove radius should be selected to match the cleaning equipment or appropriate cleaning equipment should be specified (e.g. rotating brushes are inappropriate for large radii)

Seals and expansion joints with respect to fixed walls

Size, amount and quality of silicon caulking

Material selection and thickness of wall panelling – steel sheeting with coating such as powder coating or stainless steel, aluminium, approx. 1 mm gage

Total thickness, inherent stability and maximum possible height for wall elements as well as load capacity for direct installation of small equip-ment items (e.g. paper towel dispensers, detergent dispensers, etc.)

Option to utilize interior of wall element or use variable panelling for in-stallations (e.g. IT or power cables, return air ducts, equipment utility lines)

Wall and ceiling penetrations:• Most notably: fixed pipe ways reflecting need to compensate expan-

sion and contraction with temperature changes, electrical installations etc. (see example in figure 10)

• Sealable wall penetrations for transfer pipes which are used only inter-mittently

As required, full glass walls to seal off special areas (see example of an ac-cessible return air duct for exhaust near floor level in figure 11)

Installation of doors and other components (e.g. operating panels, etc.), quality of fittings, accessibility, ability to be cleaned

Installation of windows and seal effectiveness, type of glazing and win-dow size (glazing flush with surface on one or both sides, safety glass, in-stallation of blinds, etc.)

Installation quality of ceiling elements: lighting, filters, sprinklers, etc. flush with surface or protruding

Defined load limits for ceiling – walkable for repair and exchange pur-poses, type of suspension grid



Figure 9 Checklist for wall and ceiling systems (cont.)




The stress factors for working in clean rooms have already been identified as unchanging lightingconditions and bright surfaces. Possible solutions include LED lighting, which can be colourchanged/adjusted as well as the colour design of cleanroom walls and ceilings.

For low ceiling heights (installation in existing buildings) sufficiently sized well sealing openings to floor (a ceiling with crawl space is hardly ever used – access to or crossing of installations is very difficult and is counter to GMP philosophy of easy maintenance and inspection)

Quick assembly and limited debris from construction, foil covering of the elements up to the point of completion.

Level of effort for installation, dismantling and changes

Easy to clean and resistant to detergents and disinfectants used (disinfec-tion with wipes, gassing or fogging)

Noise absorption values e.g. resulting from absorber packs sealed in foil in the walls or ceiling

Acceptance by agencies

High level of acceptance by personnel

Figure 10 Example of a seal for a hygienic pipe penetration in a wall or ceiling (source: Mogema GmbH&Co.KG, D-88239 Wangen, www.mogema.de)



Figure 9 Checklist for wall and ceiling systems (cont.)




1.5.1 Wall cladding, coating

For new construction, but also for remodelling and renovations in existing structures the construc-tion industry offers• wall, ceiling and floor coatings and• wall cladding made of modular panel elementswhich are attuned to the needs of the pharmaceutical industry. Existing concrete walls as well as tiledor plastered walls can be coated or planked in the same way as new plasterboard or even chipboardwalls.

Media ducts as well as window and door elements can be seamlessly integrated into the wall clad-ding. Likewise, jointless connections of wall coatings with a floor covering without corners andedges are possible with a radius cove (see example in figure 12), a vertical or a triangular baseboard.

Figure 11 Exhaust designed with glass panels with air withdrawal in proximity to floor

Figure 12 Radius cove with wall cladding (source: BARiT Kunstharz-Belagstechnik GmbH, D-73709 Esslingen, www.barit.de)




When cladding or coating existing walls for pharmaceutical cleanroom applications, the followingfactors should be considered especially:• High-quality moisture proof coating resistant to detergents and disinfectants• Easy to apply and durable attachment to foundation• Standard finish around window and door frames is established as a flush installation for higher

cleanroom classes (C/ISO8 and higher)• Design and integration of installations such as lighting, cable trays, pipe ducts, etc.• Special finishing work at baseboards, at transition to ceilings as well as scratch and ram guards if

integrated in the wall• For refrigerated or cold storage rooms, check the resistance to temperature variations (from ap-

prox. +25 °C to about –20 °C) relative to expansion and brittleness.

Coatings are a quite acceptable finish design for production facilities, whereby an almost jointlessexecution is possible. Coatings are particularly suitable for refurbishments.

Another possibility is wall cladding made of modular panel elements, which are attached to thesupporting wall with the aid of special profile elements (see example in figure 13). They are usuallycomparable to standard partition walls made of system components in terms of their appearanceand properties. The joints between the panels are sealed in the same manner as with system wallsand they also comply with international GMP standards.

Figure 13 Example structural design of retrofit panel wall cladding (source: OCTANORM-Vertriebs GmbH, D-70794 Filderstadt, www.octanorm-reinraum.de)

PVC 2 mm

Aluminiumd = 1.2 mm

PU




1.5.2 Wall systems

Over the past several years, wall and ceiling systems have become the established state of the art infinishing technology. The numerous manufacturers of such systems also offer solutions that are suit-able for fire zones and large, high rooms – such as warehouse storage rooms. Wall and ceiling sys-tems are flexible when it comes to planning and installation; subsequent modifications can be madequickly and easily.

The most common application is a "room-within-a-room" solution. This means that a conventionalbuilding made of concrete or brick with columns and support structures serves as a shell, and theclean rooms are fitted with system walls and ceilings inside it. To be able to benefit from the advan-tages of a walkable ceiling with fixtures, appropriate heights must be planned for the structure. A fur-ther advantage is the short assembly time at the construction site and the possibility of plan changesuntil shortly before assembly. As they are state of the art, there is little need for discussion with theauthorities.

Wall systems made from metal panels are typically constructed according to one of three designprinciples:• mono-block• band grid• axis grid

The last-mentioned type is the most commonly used. Typically, the choice is made based on thedesired design finish to achieve a sealed cleanroom surface.

Glass walls made of single-pane safety glass (SPSG) were still a ground-breaking achievement inthe nineties, but today such fully transparent systems are offered by several manufacturers. Duringoperation, it is often the case that special collision protection is not always necessary, as the employ-ees are more "cautious" with glass. Due to their full transparency, SPSG wall systems often allow sim-pler visual communication and natural lighting into rooms with lower ceilings.

When cleaning, make sure that no streaks remain. Although streaks are not a sign of poor cleaning,people tend to equate optical clarity with the effectiveness of cleaning.

In figure 14 you will find an overview of the most important information for each of the three systems.

Variant Design details

Mono-block • Compact element made of two coated steel or stainless steel panels completely filled with inserts made of the following materials:• Polyurethane (PU) foam,• Expanded polystyrene (EPS, styropore)• Epoxide resin• Mineral wool• Gypsum board• Aluminium comb• or combinations thereof

• Elements connected with dovetail joint system (integrated in the panel or with connector profiles)

• Defined silicon beads at the element butt joints• Installation elements prefabricated according to plan (see figure 18)• Door elements most often include an integrated frame with the door• Wall cladding sometimes available using thinner panels

Figure 14 Comparison of wall system variants




Band grid • Band profiles between the wall elements (twice the number of seams)• Band profiles can be opened to one side without influencing the status of the

room on the other side• Access to dead space possible from one side for subsequent utility installations• System appropriate for wall cladding

Axis grid • Lower number of seams• One-sided disassembly of the cladding not possible• System appropriate for wall cladding

Glass walls • Safety glass panels built according to plan• Panels are typically framed• Cutaways and pass throughs only possible if pre-fabricated – later adjustments

very difficult

For all alternatives

• Most often prefabricated according to drawings• Floor profiles are installed directly at the floor (see figure 15)• Baseboards for slope compensation• Recessed floor installation to enable seamless finish (see figure 16)• Ceiling connection with height compensation (see figure 17)• Cutouts for installations prefabricated, but also possible during installation using

frames

Figure 15 Wall element with simple floor rail installation

Figure 16 Wall element with recessed baseboard

Variant Design details

Figure 14 Comparison of wall system variants (cont.)




1.5.3 Ceiling systems

There are different suspended ceiling system variants available for cleanrooms:

Metal clamped cassette ceilingsThis simplest and most cost-effective variant can easily be used in cleanrooms. The metal ceiling pan-els, with or without integrated seal, are clamped in concealed supporting profiles, sealed with sili-cone and are characterised by their low weight. They are mainly used as cladding for installationsclose to low ceilings, they cannot be walked on, but can be easily dismantled (figure 19).

Band grid ceilingBand grid ceilings designed either using longitudinal band grids or arrayed band grids are the mostfrequently used types in pharmaceutical plants. The ceiling panels can be made of various materials:aluminium, stainless steel, coated steel.

Load capacities from 150 up to 250 kg/m² can be realised depending on the support profiles used, thesuspension grid (usually 1.2 m x 1.2 m) and the panel sizes. An example of the system structure of a walk-on grid ceiling can be seen in figure 20. A view of the utilities level above a walk-in cleanroom ceiling isshown in figure 21. Figure 22 shows the bottom view from the cleanroom side.

In the case of designs with pre-installed node elements for the corner connections, feedthroughs forsprinkler nozzles, instrument connections for filter leakage tests, etc. are possible at the nodes.

Figure 17 Wall element with ceiling installation profile

Figure 18 Cross section of installation components including pre-installed electrical outlets




Some manufacturers offer grid track systems for installation with LED lighting (figure 23). The ceilingelements remain free for other installations such as filter boxes or filter fan modules and the roomillumination can be distributed over the entire area according to the grid dimensions.

Gridless monoblock ceilingSandwich panels filled with insulating material correspond to the structure of the monoblock wallelements (for view of ceiling, see figure 24). A disadvantage of this system is its low flexibility. The cut-outs for fixtures (lights, filters, etc.) are made according to the plan drawings – changes during instal-lation are possible but require careful work and in some cases replacement of the elements.

Figure 19 Clamped cassette ceiling during installation

Figure 20 Design concept of a walk-on band grid ceiling

1 = 2 = 3 = 4 = 5 = 6 = 7 =




Monoblock ceilings are sometimes installed directly on the monoblock wall elements. This canreduce the number of suspension hangers required, however the load bearing capacity has to bechecked whenever the walls are disassembled or moved.

Figure 21 Walk-on grid ceiling with utilities installations viewed from above

Figure 22 View of a band grid ceiling from below with installed components




1.6 Windows and doors

The same surface requirements apply to windows and doors as to wall and ceiling systems. Theyshould be designed and installed in such a way as to avoid inaccessible areas for cleaning. Concern-ing the cleanly grouted surfaces of windows, cloths used for wiping should not lose fibres from abra-sion or adhesion, neither should it occur that residues of cleaning agents remain in the surfacerecesses.

1.6.1 Cleanroom windows

Windows are usually integrated as double-pane safety glass into the double-faced wall elements andexhibit no protrusions where deposits may accumulate (see figure 25). Ready-made and sealed doublepane elements can be integrated into the wall (commonly used in monoblock systems) or each pane canbe inserted into each wall side and sealed with installation profiles and gaskets as shown in figure 25.

Windows constructed with frames are hardly in use any more and rather unusual in class C/ISO8 orhigher cleanrooms. Single-pane glazing with corresponding profiles (no horizontal surfaces, figure26) is definitely a feasible and more cost-effective option.

Figure 23 Grid track for installation of LEDs (source: OCTANORM-Vertriebs GmbH, D-70794 Filderstadt, www.octanorm-reinraum.de)

Figure 24 View from below of monoblock ceiling with installed fixtures

LED




Drutex is currently offering a concept version of a technical innovation that follows the trend of the"IoT" (Internet of Things). An interactive window, which allows multimedia content to be displayeddirectly in the window glass and can be operated like a tablet, will be available for regular sale in thenear future. This means that SOPs, drawings (see figure 27), process steps, messages and much morecan be made accessible directly in the clean room for the production area and may even replace thecomputers in the clean room in the future.

Figure 25 Design principle: double glazed safety glass in a wall element

Figure 26 Design principle: single pane safety glass in a wall element




1.6.2 Cleanroom doors

Hinged doors, single or double-leaf with inactive and active leaves, striking plate, hinges and handlesets are the most frequently used doors in cleanrooms (for designations, see figure 28). The frames areusually designed as block frames (flush with the wall element, usually in monoblock systems) or asclasping closed frames (wrap-around frame profile encloses the wall element, figure 29).

The integration of components in the striking plates or frames for so-called asynchronous interlock-ing, which prevents the simultaneous opening of multiple doors, is already regarded as a technicalstandard today.

The opening sides classified as DIN left or DIN right are shown in figure 30.

Figure 27 Interactive window pane (Drutex S.A., www.drutex.de)

Figure 28 Designations of door components




For fire protection requirements within the clean room network, clean room doors are also availableto meet the corresponding specification. Fire doors are classified as T30 (fire-retardant), T60 (highlyfire-retardant) or T90 (fire-resistant) doors. The type to be used is specified by the authorities.

Cleanroom doors can be equipped with drives for automatic opening by sensors or by manualcontrol units and also including door closers. Monoblock systems often offer the possibility of inte-grating door closers into the panel. These are not visible from the outside, but replacement shouldbe possible.

The suitability of the drive for use in a cleanroom environment should be proven (e.g. suitabilitytest by an independent institute). The safety requirements of the European harmonized productstandard EN 13241 must be complied with. Thresholds or stop rails on the floor are not recom-mended.

Whether door leaves are installed flush with the wall element on one or both sides is not impor-tant and also depends on the frame used. A three-dimensional adjustability of the door leaves is rec-ommended for optimum sealing and fitting into the frame. For sterile and comparable productionareas, the doors should have smooth surfaces, minimally angled frames and easy-to-clean surfacesand seals.

A retractable bottom seal (figure 31) in hinged door leaves is often requested and installed becauseof the higher sealing tightness, however it does not meet the above requirements. They exhibituncontrolled recesses in the door leaf, which are open at the end faces of the door and permit clean-ing only when the door leaf is removed.

Figure 29 Design principle of wrap-around clasping frames

Figure 30 Opening sides of doors

DIN DIN




The fixtures including bolt, latch, door locks and the hinges are often overlooked as weak points.Most doors here have uncontrolled and hard to clean openings (striking plate open towards theentire door frame).

In the following, designs for hinged doors are presented which are appropriate for cleanroom appli-cations (figure 32 to figure 36).

Figure 31 Integrated retractable bottom seal for hinged doors

Figure 32 Horizontal cross-section of a cleanroom door with removable single-sided seals and flush-mounted window (Octanorm-Vertriebs GmbH, www.octanorm.de)




Easy-to-clean standard doors with standard locks and corresponding handle sets are acceptable inGMP clean room grade D, in cleanliness classes E and F (according to WHO for non-sterile produc-tion) and in non-classified areas (CNC3 und NC4).

With regard to sliding doors Annex 1 of the EU GMP Guidelines recommends:“To reduce accumulation of dust and to facilitate cleaning there should be no un-cleanable recesses

and a minimum of projecting ledges, shelves, cupboard and equipment. Doors should be designed toavoid those uncleanable recesses; sliding doors may be undesirable for this reason.”

The word selection in the German translation of the text “sliding doors may be undesirable” wassomewhat harsher than the original English intent, which in the past has led to a general distaste forsliding doors in GMP environments there, as it was interpreted that “sliding doors are not permitted”.

Figure 33 Horizontal cross-section of a monoblock door with frame and removable two-sided seals

Figure 34 Horizontal cross-section of cleanroom door with magnetic frame as the sealing surface (Cleangrad d.o.o, www.cleangrad.si)

3. CNC – Controlled Not Classified (controlled access, but not classified cleanroom class)4. NC – Not Classified/corresponds to general uncontrolled areas with access control

Door frame

Monoblock door leaf

Seals




Practical inspection experience has shown that in most cases sliding doors as well as high-speed rol-lup doors are accepted by the agencies for cleanroom applications.

When installing automatic sliding doors, it should be considered that the drives should be installed onthe side with the lower cleanroom class (see view from side with higher cleanroom class in figure 37).

Analogously, the same recommendations apply for so-called high-speed doors (figure 38), whichroll up in the vertical direction to open and close.

Figure 35 Horizontal cross-section of cleanroom door with double seal and block frame ( Viessmann Cleanrooms)

Figure 36 Horizontal cross-section of single-sided flush-mounted hinged door with wrap-around frame (ems, D-23689 Pansdorf, www.ems-isolier.de)




Figure 37 Automated sliding door with status indicator, emergency stop and cleat (G+H Reinraumtechnik GmbH, D-67063 Ludwigshafen; www.guh-reinraumtechnik.de)

Figure 38 High-speed door with electrical drive – cleanroom certification from Fraunhofer Institute (source: ASSA ABLOY Entrance Systems, www.assaabloyentrance.de)




Horizontal sliding doors and vertical rolling high-speed doors provide a number of decisive advan-tages in cleanrooms:• They have low space requirements.• As a result of their roll-down design, they provide effective seals on all four sides.• Undesirable strong turbulent air currents and pressure swings, which often occur when opening

hinged doors, are avoided with this application.• High speed doors reduce the incursion of air and the potentially resulting cleanroom air contami-

nation to a minimum.

The following requirements are placed to achieve a GMP-compliant motorized or mechanical drivedesign:• The sliding door leaves are only attached at the upper side on a rolling carriage. Thresholds and

floor rails are not recommended.• The complete drive unit and support rail should be enclosed according to dust protection stand-

ards, be sealed as well as possible and be mounted on the side of the wall with the lower clean-room standard.• Technically, it is possible to connect the housing to the exhaust air pipe and to extract the parti-

cles generated therein (from abrasion) in a targeted manner (i.e. at "negative pressure" comparedto the clean room).

• The housing of the drive parts should be easy to open for inspection and cleaning purposes andalso be easily accessible for cleaning.

The following safety aspects should be considered or installed• Safety specifications according to the European harmonised product standard EN 13241. The level

of safety can be improved further by using a presence recognition system.• Emergency stop switch• Back-up battery or manual emergency opener• Regular safety checks according to agency, manufacturer and internal safety specifications

1.7 Floor systems

Cleanroom floors are generally classified according to the surface facing the cleanroom. The floorstructure itself – from its impermeability to its load-bearing capacity and its static requirements – ispart of the building construction and is not related to the topic of cleanrooms.

To assure the quality of installation for the described floors, the following motto can serve as a guid-ing principle for competent construction supervision "produce quality at every stage of the processand do not just test it at the end" (figure 39).

Checklist for floor systems Meets expectations?


Highest level and defined quality of the floor screed (example: ZE class according to DIN 18560, flatness according to DIN 18202 – or preferably according to separate agreement), clean, dust-free surface

Defined screed residual moisture content attained before next process-ing step (determine and document)

Figure 39 Checklist for floor systems




1.7.1 Design variants

The more precisely the requirements are known and described in the URS, the more accurately they canbe implemented. The guidelines for cleanroom technology provide very different recommendations forcleanroom floors. This makes it all the more important to consult the right experts in order to specify therequirements.

For the overall design of a pharmaceutical industrial floor, additional requirements outside theEurocode specifications must be included in the URS, e.g.:• Special structural criteria and project specifications (a special surface may be specified, e.g. cast

resin, rubber, etc.)• Resistance to moisture (wet conditions during cleaning and/or production)• Slip resistance (appropriate for the type of cleanroom shoes used)• Temperature and humidity at rest and during operation (e.g. frequency and intensity of tempera-

ture or humidity fluctuations)

Use only compatible additives and adjuvants: bonding bridge, filling compound, adhesive; demand proof of suitability even in case of minor changes!

Experienced contract taker and motivated/trained construction personnel

Regular training updates for the construction personnel (e.g. at the floor-ing material supplier’s site. A contractor which can certify that its employ-ees are trained is to be classified as competent)

Processing instructions for steps following completion of the plane floor screed, also reflecting procedures for installed elements and interfaces with neighbouring trade work.

Defined joints as necessary (depending on type of floor finish and neigh-bouring trade work)

Maintenance of a construction site journal including documentation of processing conditions used

Intermediate quality assurance testing (example: Peel test according to EN 1372 for PVC sheet coverings, adhe-sive force according to EN 13813 for coverings fabricated on site etc.)

General responsibility for all floor installation work carried out by one provider

Definition of the warranty period (warranties are only regulated by law in direct consumer business!)

Procedure for basic cleaning and cleaning inspection

Mutually agreed final acceptance test according to previously negotiated parameters and associated specifications (with ranges and definitions re-garding statistics)

Checklist for floor systems Meets expectations?


Figure 39 Checklist for floor systems (cont.)




• Durability according to special project specifications (distributed and point loads, mobile or static,rolling, sliding)

• ESD5 safety, electrostatic specifications. The floor covering must maintain constant conductivity lev-els throughout its service life (for electronic components, static charges from wearing insulatingshoes, using insulating wheels, etc.).

• Cleanability according to operational needs (chemical resistance)

The resulting specifications to achieve an optimal construction implementation, such as• Surface finish,• Insulation and sealing technique,• Arrangement of expansion joints,• Electrostatic properties (insulation resistance for protection of persons, ground leakage resistance)• Type, arrangement and thickness of layers in the overall structure,• Compatibility of the individual layers and the timing of their application,are all to be seen as part of the FDS and should be specified by potential contract takers according totheir expertise.

The quality of the substrate is decisive for the quality of the surface covering and thus for the dura-bility of the overall structure. The requirements for the substrate – usually a levelling screed – arespecified below:• Essential pipes6 should be fixed, immobile and without crossings• Straight, aligning, complete floor joints, whenever possible installed as “inlay joints”, without level

changes• Cleanly swept surfaces: free of contaminants such as oil, coating residue, mortar residue, blooms

and visible dust• Free of cracks, in case cracks are present, these are to be repaired by load-bearing adhesion• Defined surface strength• Defined levelling quality according to operational requirements• Installed metallic components made of CrNi steel (recommended minimum material quality:

standard grade 1.4301)

An exemplary basic structure of a suitable industrial floor is shown infigure 40. The brackets indicatecomponents that are required depending on the application.

There are various design alternatives commonly accepted for industrial flooring in pharmaceuticalplant construction using commonly accepted surface coverings:

Composite construction with load-bearing concreteThis involves a load-bearing adhesion of the top layer to the jointless levelling screed and adhesivebond of the screed to the load-bearing concrete (figure 41). This variant is suitable for:• High cleanliness specifications (up to cleanroom class A)• High-load floor coverings• Occasional wet conditions during cleaning – but not “wet” operations

For special applications, such as cold storage rooms, it is recommended to make a recess in thescreed in order to avoid thermal transmission and material strain.

5. ESD – Electrostatic Discharge6. Pipes imbedded in screed should be avoided whenever possible. Otherwise it is recommended toinclude stop valves so that operation of other equipment using the same system is not impaired in case ofdamage.




Design using separating layer between non-reinforced screed and load-bearing constructionThis is a load-bearing adhesion of the top layer on the levelling screed and between the screed andthe separating layer (figure 42).• Two-layer sealing sheet compensates for movement• Recommended for continually wet operating conditions and• For high dynamic loads.

Figure 40 Basic structure of an industrial floor

Figure 41 Installation concept compound screed, seamless

COM

POSI

TE is

sec

ured

by

use

of

app

rop

riate

mat

eria

l and

co

rrec

t pro

cess

ing.

WEAR-LAYER-> Hardness = f (traffic load, thermal and chemical stress)

ADHESIVE LAYER

As required LEVELING of irregularities from – Filler application – Removal of mortar foundation

As required NEUTRALISATION of screed alkalinity

LEVELING LAYER (50 mm)-> Thickness = f (Pressure and torsion loading)

As required BARRIER LAYER for WET OPERATIONS

Or

As necessary ADHESIVE LAYER

LOAD BEARING LAYER = Floor foundation with sloping concrete

Synthetic resin cove




1.7.2 Types of surface covering and examples of installation alternatives

Of the many possible types of floor surface covering, the following are the most commonly used inthe pharmaceutical industry:• Ceramic floors

Tiled floors with tiles set either “floating” or “grinding” (contacting tiles), if applicable, using groutwith electrical discharging capacity.

• Synthetic resin bonded floorsImpregnation, sealing and above all, synthetic screed floor.

• Panel und sheet coveringsPVC, modified PVC and rubber, welded, gap-free

• Cement bonded floorsNormal screed (vacuum screed), synthetic modified screed, hard material screed

• Metal floorsMade of CrNi steel sheets with stamped surface pattern

• Poured resin floorsGood bonding to substrate, very good durability versus chemicals

In the following eight of the most commonly used cleanroom floor types and their common variantsare presented.

Figure 42 Installation concept screed on separating layer

Cellulose stringElastic caulkEdge strip

Seal coat Screed, non-reinforced 2 layers of PE foil 0.1 mm Asphalt sheet Asphalt pre-coat Concrete foundation




Example 1: Hard aggregate screedThis flooring is appropriate for warehouse and high-load transport areas in low cleanroom class areas(Class D).

Example 2: Ceramic tile floorsCeramic tile floors with synthetic grout (figure 44) were commonly used as cleanroom flooring in thepast. They are appropriate for use in wet operations and can withstand high loads. For cases of con-tinual wet conditions, a moisture barrier should be installed below the levelling screed.

Figure 43 Hard aggregate screed for warehouse areas and high-load transport areas

Figure 44 Electrically discharging tile floor with defined conductive grout

Surface ground and polished

Mineral layer > 15mm (5 kg/m² Korrodur)

Mineral bonding bridgeScreed surface ball peened

Composite screed ZE30>30 mm

Adhesive layer

Load bearing concrete

Grout: epoxy resin with soot additiveTop layer: panels with linking rodsAdhesive layer: epoxy resin with soot additive Copper wire

Composite screed, grade ZE30/ZE40, >25 mm, ball peened and vacuumedMineral or epoxy resin bridge





Example 3: Synthetic screedFloors made of synthetic screeds, which are produced by applying fillers (figure 45), are the mostcommon cleanroom floors in the pharmaceutical industry, which are known under the trade name"pharma terrazzo".

The surface can be modified in such a way that a slip resistance level of up to R12 is achieved. Typicalvalues for slip resistance are R9, R10 and in wet areas also R11 and R12.

It must be taken into account that the cleaning ability decreases with increasing slip resistance. Thismakes a compromise necessary between the required hygiene level and a surface suitable for wetcleaning or wet production with regard to occupational safety.

In addition to epoxy resins, plastics such as polyurethanes and their mixtures can also be used.With special formulations or additives, such as carbon fibers, metal chips, etc., a defined conductivitycan be achieved on the surface. The thickness of the plastic layer can be adjusted to suit the desiredload capacity by filling or casting.

Example 4: EP cast floorFigure 46 shows the structure of an electrical discharging cast epoxy resin floor.

Figure 45 Synthetic screed made from epoxy resin and quartz sand mixtures

Figure 46 Electrical discharging EP cast floor

Sealed surface

Epoxy resin mortar layer, conductive, d = 4 mmfor heavy loads, mechanically installedConductive primer coat epoxy resin

Screed surface ball peened

Adhesive layer





Example 5: PVC sheet floorFloors made of PVC sheets with welded joints are preferred in areas for dry operations with low loads,personnel airlocks or similar applications (figure 47). Special attention should be paid to the possibleemission of plasticizer gases.

Example 6: Electrical discharging seamless PVC floorsTo produce dissipative PVC floors (figure 48), the PVC is compacted under high pressure and at hightemperature; in doing so, it loses a portion of the plasticizer. Conductive filaments are introducedinto the compound to achieve the surface conductivity. Sheets and profiles are homogeneously anddurably welded together without joints. Any cleaning method can be used.

It is possible to repair damaged areas with replacement material by welding without any problems.Depending on the thickness of the layer, it is possible to mechanically clean stubborn soiling such astracks by using grinding wheels.

Figure 47 PVC sheeting floor for dry work areas

Figure 48 Electrically discharging PVC floors (e.g. forbo ®)

Plastic sheet, welded jointsEpoxy resin adhesive

Dissipative, compacted plastic nearly free of plasticizer

Dissipative screen

Acrylic adhesive

Screed surface, ball peened

Bonding layer





Example 7: Electrically discharging (ESD) rubber floorsThe electrostatic behaviour of discharging rubber floors is suitable even for very high demands onthe cleanliness class. These floors are characterised by permanently tight welded seams, high elastic-ity and high slip resistance from R9 to R10.

Studies show that rubber floor coverings have an enormously smooth and dense (pore-free) surface.Due to their high long-term elasticity, these floor coverings make it easier for personnel to stand forlong periods of time and contribute to ergonomic workplace design.

Example 8: Vacuum screedThe designation “vacuum screed” comes from its fabrication process: after application, the wetscreed is treated by smoothing it out while applying a vacuum suction (figure 50).

The dry surface is sealed by impregnation with plastic. Transport equipment must have rubber tyresand the seal must be renewed occasionally. The screed is preferably used in lower cleanliness classes,storage areas and other ancillary areas.

The great advantage of such floors is that they can be brought to a higher level of cleanliness by ballpeening and suction for the installation of a bonding bridge with an additional top layer.

Figure 49 High-load ESD sheet floor covering made of rubber (Nora®)

Figure 50 Sealed vacuum screed for storage areas and other ancillary areas – cleanroom class F

Noraplan al 2 mmLatex adhesive, conductive, imbedded: copper wires connected to building grounding cables

Foundation (dispersion or epoxy)

Screed surface ball peened

Bonding layer

Substrate (screed or concrete) surface vacuumed and ball peened

Seal coat < 0.1 mm

Screed ZE40 (surface compacted by mechanical smoothing and vacuuming)

Mineral bonding bridge

Load bearing concrete B25




1.7.3 Laying techniques and design variants

As a rule, the laying of sheeting has several organisational and technical junctions, which can lead tothe following serious errors, particularly in the case of inadequate construction supervision:• defective screed quality• unclean substrate, defective levelness• inappropriate adhesive used• copper conductor improperly laid or broken (for ESD floors)• insufficient filler• inadequate contacting coverage with adhesive• defective seam welds

When refurbishing existing floor covering or installing new ones the following procedures are to befollowed:1. Examination of the exposed levelling screed for compressive strength and adhesive tensile

strength versus the load-bearing concrete (see figure 43 through figure 49).2. Preparation of substrate according to condition of the screed surface:

• milling or• ball peening or• milling and ball peening• followed by vacuum cleaning (HP vacuum or wet vacuum) to remove dust

3. For cases in which the screed is completely intact• High pressure water spray-cleaning and drying followed by vacuuming as in No. 2

4. For cases in which the surface is contaminated with grease or oil• If applicable, remove impacted screed and renovate and treat as in No. 2

The quality and service life of a professionally installed industrial floor are primarily determined bythe quality of its interfaces to the subfloor and to existing floors. It is precisely these interfaces thatare stressed by dynamic loads.

Special attention should therefore be paid to the design and quality of the floor fixture installationwork:• Transitions to other types of flooring (example in figure 51 and figure 52)• Connections to walls (example in figure 53)• Building expansion joints and apparent joints• Installation joints between two identical floor types• Installations in floors (ram protection, bollards, inlets, breakthroughs, etc.)

Figure 51 Transition from tiled floor to sheet covered floor

2075

5

100

6035

5

1002010

5




The quality of joints in load-bearing concrete is of particular importance (figure 54), as they are sub-ject to particularly high dynamic loads. Above a certain size of the field to be worked, joints are nec-essary for structural reasons.

The quality of the joints in the top layers of the flooring must be adapted to the technical require-ments of the building and the loads occurring during operation (figure 55 through figure 57).

Figure 52 Transition from synthetic resin to tile floor

Figure 53 Wall connection for tile floor

Figure 54 Contraction, transverse and longitudinal joints in loadbearing concrete

120 mm40 mm

20 –

40

mm

5 –

10 m

m

2075

5

10

40 m

m

4 mm

(40/4) (40/4)




Constructions such as ramming protection and bollards are mounted directly on the concrete of theunfinished floor to ensure the necessary stability.

Floor openings are constructed as double pipes (sleeve pipe, slip-on pipe, figure 58).

Figure 55 Floor expansion joint cover (e.g. type Migua, https://www.migua.com/en/products/migutec/)

Figure 56 Expansion joint for tile flooring

Figure 57 Expansion joint in traffic areas with tile flooring

ConcreteSynthetic resin mortar

Migua-profileCement screed

Cement screed

300 mm300 mm

300 mm10 –20 mm

10 mm




Flat floor troughs (figure 59), deep box troughs and floor inlets (figure 60) are enclosed in plastic withtheir metal collars. The connection of the floor covering shall also be tight. When selecting the covers forthe floor inlets, the load class must be taken into account – it must meet the operating requirements.

The GMP compliant installation of a floor drain is impacted by the following special design require-ments:• Material made of CrNi steel (1.4301)• Odour trap and dirt trap can be pulled out fully

• optional: Closing plug for the downpipe• The downpipe is accessible for disinfection (steam or chemical)• Hermetically sealed lid with rubber ring seal

Figure 58 Floor pass through opening with sealed double pipe

Figure 59 Installation of flat floor troughs

Figure 60 Installation of floor inlet

ca. 20 mm

20 m

m

50 mm

15%

100 mm

± 50 mm

± 2

0 m

m




1.7.4 Acceptance testing of floors

The user or his planner determines what is inspected during acceptance testing and with what spe-cifications. The definition of the specifications, such as the electrical/electrostatic properties, is usu-ally performed by experts.

The acceptance testing for cleanroom floors regarding its functionality can be performed as follows,for example:1. Acceptance testing according to contractually agreed test norms and guidelines versus the fol-

lowing properties:• electrical/electrostatic properties• flatness• screed quality• tensile bond strength• slip resistance• residual impression depth, if applicable

2. Document reviews (certificates, test reports), for cases where testing on site is not sensible or pos-sible. Examples include:• Fire prevention or noise protection characteristics• Grinding losses/wear resistance• Thermoshock resistance• Chemical resistance etc.

3. Visual inspections, such as:• Levelling and edge offset on fixtures according to agreement• Floor transitions and wall connections as shown in sample/as drawn• Cleanliness after basic cleaning as agreed, cleaning result after fine cleaning (and disinfection if

necessary) as agreed/if necessary according to USP• Freedom from cracks according to agreement, and others.

In the case of quantifiable properties, the permissible deviation from the target value shall be indi-cated in each case, and information on statistics, e.g. number of samples, shall also be provided.Examples include values for the adhesive tensile strength in the case of synthetic floor screeds orsheet flooring.

Figure 61 shows an example of the acceptance parameters for a GMP-compliant (jointless) ESDrubber sheet covering.

Technical Specifications• Electrostatic charge affinity/voltage of the system footwear + person + floor:

• According to IEC 61340-4-5 and ESD-STM 97.1: <10 V (semiconductor industry)• Electrostatic properties according to EN 1815: <1 kV (example from micro-electronics)

• Ground discharge resistance according to EN 1081: 106 to 9 x 107

• Insulator resistance according to VDE 0100/part 610: >5 x 104

• Fire behaviour characteristics according to EN 13501-1: Cfl s1• Adhesion of surface covering to fill screed: as agreed (or QS from producer as applicable)• Residual impression according to EN 433: < 0.05 mm• Abrasion according to EN ISO 4649/5 N load: < 180 mm3

GMP characteristics for cleanrooms• Inspect for “smooth surfaces free from cracks”: visual, with optical devices if applicable• Test for impenetrability: visual, but mostly by reviewing expert certification• Durability with regard to defined impact of specified detergents and disinfectants

Figure 61 Acceptance testing parameters and specifications for seamless laid ESD sheet floor covering for critical areas




1.8 Application areas of construction components for different cleanroom classes

A proposal is made in figure 62 for the application of the described components in the differentcleanliness classes in pharmaceutical plants. The classification is based on the surfaces facing thecleanroom. A risk assessment (example in figure 63) covering cleaning, disinfection and proximity tothe product, however, may lead to different results.

The cleanliness classes shown in figure 62 are described in chapter 3.D Air Cleanliness Classes andGrades and are based on the information in Annex 1 to the EU GMP Guidelines and ISO 14644. ClassesE and F are taken from the WHO guideline for non-sterile manufacturing and contain only microbiallimits. The designations CNC (see footnote 4) and NC (see footnote 5) are currently proposals underdiscussion.

Cleanroom class according to EU GMP Guidelines

A B C D ECNC

FNC

Equivalent ISO classification (defined particle limits for condition “in operation”)

(5)4,81

7 8 (9)2 – –

Legend:X: recommendedO: optionally recommended, not mandatory (risk assessment result)–: not defined, not required

1. Walls

Wall feedthroughs – kept to a minimum number X X X X O O

All feedthroughs are closed off with elastic seals X X X X O O

In areas exhibiting low-turbulence plug flow air (unidirectional airflow – “laminar flow”) the verti-cal wall surfaces should not present an aerody-namic obstacle and hinder airflows thereby caus-ing turbulent conditions

X O – – – –

Smooth, flat, impervious, non-porous, non-absor-bent or gas-emitting surfaces which are resistant to the detergents and disinfectants used

X X X X X –

Monoblock or twin shell system walls with de-fined specifications for baseboard and ceiling juncture

X X X O O –

Twin shell system walls with defined specificati-ons for baseboard and ceiling juncture

X X O O O –

Wall cladding made of single-shell system wall components

O O X X O –

Wall surface coating O O O X X X

Gypsum board stud walls, smooth, coated and cleanable

– – – O O X

Figure 62 Examples for the assignments of construction components to appropriate cleanliness classes




Cove radius transition to floor and/or ceiling• A cove radius transition is generally viewed as

the preferred installation design. Recent research has shown that “straight corner junc-tions” make effective cleaning possible, while cove radius installations and inappropriate cleaning equipment tend to result in worse cleaning results. Radius coves are much more difficult to fabricate and install (cost, time) ver-sus conventional systems.

O O O – – –

Avoidance of horizontal surfaces above the critical zone (production area). Any unavoidable installa-tions should be clad and sealed up to the ceiling.

X O O – – –

Expansion joints and joints between different materials must be elastically sealed.

X X X X O3 O

2. Ceilings

Band grid ceiling system X X X O O –

Monoblock ceiling system X X X O O –

Metal clamped cassette ceiling with sealed joints – – O X O –

Metal clamped cassette ceiling without sealed joints

– – – – O X

Ceiling connections are to be constructed with elastic seals

X X X X O O

Walk-on ceiling for maintenance purposes – X X X O –

All installations and pass throughs constructed with elastic seals

X X X X O O

Surfaces smooth, tight, non-porous, non-absor-bent or degassing and resistant to the detergents and disinfectants used.

X X X X O O

Maintenance access openings with airtight seals –4 – O X X X

3. Lighting

The lighting intensity must be adapted to meet the requirements of the process. Workplace-re-lated laws must also be taken into account.

X X X X X X

Surface-mounted lights should not obstruct the air flow.

X X O – – –


A B C D ECNC

FNC


(5)4,81

7 8 (9)2 – –

Figure 62 Examples for the assignments of construction components to appropriate cleanliness classes (cont.)




The replacement of the lamps should take place outside the clean area.

X O O O O –

4. Ventilation fixtures

Supply air and exhaust air diffusers installations (with or without filter) must be vibration-free and sealed.

X X X X X X

Exhaust air extraction near the floor compatible with ease of cleaning

X X X O O –

Wherever possible, air distribution elements (perforated plates, Anemostats, etc.) should be installed flush with the ceiling or with a tight ceiling fitting. During cleaning (wipe method) the air deflector elements must not move.

– X X X O O

The connections for the filter integrity test (differ-ential pressure, aerosol feed for filter leak test) should be accessible without dismantling the air distribution elements.

X X X O – –

5. Floors

Smooth, dense, non-porous, non-absorbent or degassing surfaces which are resistant to the detergents and disinfectants used.

X X X X O O

Abrasion and slip resistance X X X X X X

Electrically discharging to avoid electrostatic charging (high charge with very dry air)

X X X X X X

Surface and point loading for the equipment used (pallet storage – surface load; pallet truck or mo-bile container – point load)

X X X X X X

Closable and disinfectable floor drains.Optional: Replace class B floor drains with sealable connections in the wall. The liquid medium is disposed of with a pump (bilge pump).

– O5 X X X X

For wet cleaning, the floor gradient must be es-tablished towards the drains.

– O X X X X

For CrNi ground sheet metal floor covering (observe anti-slip requirements)

O O – – – –

Synthetic screed, cast resin and cast floors O O O O O O


A B C D ECNC

FNC


(5)4,81

7 8 (9)2 – –





1.9 Example of a risk assessment for surfaces

The table in figure 63 shows an example of the assessment of room surfaces in terms of productsafety. The explanations and the evaluation key are given in figure 64.

Plastic panel covering with welded joints O O O O O O

Seamless ESD sheet floor covering made from compacted PVC or rubber

O O O O O O

Joined sheet or tile floor covering made from PVC – O O O O O

Ceramic blocks in cement substrate – – – O O O

Mineral screed and coated vacuum screed – – – – O O

6. Doors

No thresholds on the floor X X X X O O

Doors and fittings (hinges, door handle sets, win-dows) should not have horizontal surfaces or other hard to clean depressions or dead spaces.

X X X O O –

Flush installation in the wall system to both sides X O O – – –

Emergency exits and access to maintenance areas should be secured.

– X X X X X

Use of sliding doors – – O O O O

Use of highspeed roll-up doors – – O O O O1 ISO class 4,8 is met by fulfilling the specified limits for particles >5.0 µm2 No particle limits are defined for EU GMP class D. In general, ISO class 9 has been accepted in its place.3 Recommended in cases where room pressure is controlled to minimize leakage air amount4 Ceiling openings to access maintenance areas should be avoided in Class A and B areas5 Floor drains are not permitted in Class A, they are to be avoided in B.

Surface R1 R2 R3 R4 RPN1

Cleanroom walls 3 2 1 1 6

Cleanroom ceiling 2 2 1 1 4

Cleanroom floor (production areas) 2 2 22 1 8

Macrolon housing of isolator 2 1 2 2 8

Cleanroom doors 1 1 1 2 2

Figure 63 Example of a risk assessment for room surfaces


A B C D ECNC

FNC


(5)4,81

7 8 (9)2 – –





Countertops (e.g. compounding step) 1 1 2 3 61 RPN = Risk Priority Number, calculated from the individual risk levels:

R1 x R2 x R3 x R4 = RPN2 For the proximity to the product, a 2 was chosen for the floor. Justification: About 70% of contami-

nants are transferred via the floor. Floor deposits are stirred up by the movement of the personnel – with high air circulation rates and the resulting turbulence, there is a higher risk of contamination. If the movement intensity of the personnel is low and the level of air turbulence can be proven to be low, the value can be set to 1.

Category Risk Level

Description

R1 Size of the area to be considered, whereby the size is to be seen in relation to the total area (an enclosure of an insulator is to be judged larger in relation to the total enclosing area than a clean-room ceiling in relation to the total wall/floor/ceiling area).

3 The surface can be regarded as a large part of the total area.

2 The surface has a moderate proportion of the total surface area.

1 The surface has only a small proportion of the total surface area.

R2 Physical and chemical properties of the surface

3 The surface is very rough and has a risk of absorbing moisture. Not chemically resistant, risk of corrosion, surface prone to scratches, difficult to access for cleaning.

2 Roughness barely measurable, little or no risk of moisture absorption, re-sistant to common chemicals, no oxidation or corrosion, easy to clean, no growth of microorganisms

1 The surface is smooth, very resistant to chemicals, can hardly be scratched, is easy to clean and accessible for cleaning, no growth of mi-croorganisms.

R3 Proximity to product

3 The surface is in direct contact with the product

2 The surface is close to the product or the (open) production process

1 No contact with or proximity to the product

R4 Influence of operating personnel

3 Operators stand in direct contact with the surface during the production process

Figure 64 Legend for Table in figure 63

Surface R1 R2 R3 R4 RPN1

Figure 63 Example of a risk assessment for room surfaces




The assessment of the level of the risk priority number (RPN) may be defined as shown in figure 65.

This example for the assessment of surfaces is taken from an evaluation of the type and frequency ofsurface disinfection in pharmaceutical production and is intended to support the uniform and com-prehensible assessment of suitable surfaces. This form of risk assessment is intended as a template,whereby changes and adaptations are possible and encouraged.

2 Operators are only in contact with the surface to intervene in the process irregularly

1 Operators have no contact with the surface during the production pro-cess

RPN Risk – Level for product safety

< 6 Minimal to low risk

6 Moderate risk, no actions

R3/R4 = 3 Optional requirement:If a value of 3 is assigned for R3 or R4 without leading to an RPN > 8, a separate as-sessment and evaluation may be demanded, since a greater influence on the prod-uct is given

≥ 8 High risk – actions are to be defined regarding the cleaning procedures or a differ-ent type of surface is to be selected

Figure 65 Assessment of RPN

Summary:When planning and constructing premises for pharmaceutical purposes, building law, operational and GMP requirements must be taken into account. Good Engineering Practice offers a systematic approach to the implementation of these different requirements in practice.When selecting wall and ceiling systems, window and door elements as well as floors, the in-tended cleanliness class of the rooms concerned must be taken into account. A risk analysis and the documented assessments as well as selected measures for risk acceptance are to be used for the selection of the components.The current state of the art and special considerations for detailed design execution are presented based on construction examples.

Category Risk Level

Description

Figure 64 Legend for Table in figure 63 (cont.)



Contributors

Harald Flechl, Senior [email protected] [email protected]

Air conditioning technician – clean room technology

Harald Flechl is a senior engineer with more than 30 years of professional experience in planning,implementing and maintaining ventilation systems in the pharmaceuticals, electronics and healthcare industries. From 2008 to 2017, he was responsible for the design of building technology systemsand clean room and support systems at Shire plc. Mr Flechl retired in 2018. However, he continues to write and speak at conferences. As an ISPE mem-ber, he prepares expert reports and provides consultancy services.

Mr Flechl graduated from the Vienna School for Higher Technical Education (HTL) with an Engineer-ing degree. In 1974, he started working in the area of industrial plant engineering. He moved to Luwain 1980 where he was primarily involved in the further development of a patented sterile air distrib-utor for low-turbulence displacement flow. In the following years, he worked in a number of differentcompanies in the areas of customer services, facility construction and maintenance. In 2006, he tookup a position at Shire (formerly Baxter AG/Baxalta) in the media supply department. Since 2012, hehas been working as a "Global Engineering" expert with responsibility for technical design, energyoptimisation and the life cycle aspects of the heating, ventilation and air conditioning systems, andcompressed air systems.

Mr Flechl has completed a large number of training courses in the areas of contract law, air condition-ing and quality assurance. He has worked at the Austrian Standards institute and as a court-certifiedexpert for air conditioning and clean room technology. In addition, he provides presentations on airconditioning technology for staff training courses, compliance, technical implementation and lifecycle considerations.


Index


Index

Cchecklist

- floor systems 30- wall and ceiling systems 12

clean room floors- acceptance testing 43

cleanroom- components, see cleanroom construction 2- qualification 8

cleanroom construction- agency requirements 3- ceiling systems 19- Eurocode standards 3- financial aspects 9- floor systems 30- floor systems checklist 30- GEP 6- GMP requirements 4- high-speed doors 28- hinged doors 26- life cycle costs 9- list of specifications 7- process flow chart 8- qualification flow chart 8- requirements 6- room book 7- sliding doors 27- standards 4- wall and ceiling systems 12- wall and ceiling systems checklist 12- wall cladding 15- wall systems 17

cleanroom doors 24- bottom seal 25- drives 25

cleanroom floors- design alternatives 32- design variants 31- laying techniques 39- substrate 32- surface covering 34

cleanroom planning 11- Building Information Modelling 11- virtual reality 12

cleanroom windows 22construction components

- procurement 6- selection 5- usage for cleanroom classes 44

EEurocode standards 3

Ffloor drain 42

GGEP

- cleanroom construction 6

Hhuman resource management 50

Ppackaging materials 50

Rrisk assessment

- surfaces, example 47

Ssurfaces

- risk assessment 47



German National Library Cataloguing in Publication DataA catalogue record for this book is available from the German National Library at http://dnb.ddb.de

ISBN: 978-3-95807-182-7

First edition 2020

The content is an excerpt from the GMP Compliance Adviser, the world's largest collection of GMP knowledge.

© 2020 GMP-Verlag Peither AG – All contents, in particular texts, photographs and graphics, are pro-tected by copyright. All rights including reproduction, publication, editing and translation remain reserved – GMP-Verlag Peither AG

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This publication has been carefully compiled. Nevertheless, the authors and publisher accept no lia-bility for the correctness of information, references and recommendations as well as for any typogra-phical errors.


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