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					TABLE OF CONTENTS

                                                                                                                                            Page

1.     Introduction and Objective .....................................................................................................3
2.     Zone Concept ...........................................................................................................................4
3.     The Design of the System .......................................................................................................5
   3.1 User Requirement Specification (URS) ..................................................................................5
   3.2 Factors to be considered in Design ........................................................................................5
       A. Quality of the Intake Air .......................................................................................................5
       B. The Prevailing Wind ............................................................................................................5
       C. Climatic Conditions ..............................................................................................................5
       D. Overall Design of the Air Handling System .........................................................................6
       E. Product Specific Requirements ...........................................................................................6
       F. Air Flow Regimens ..............................................................................................................6
       G. Air Change Rates ................................................................................................................7
       H. Filtration ...............................................................................................................................7
       I. Localised Area Design.........................................................................................................8
       J. At Rest and in Operation Conditions ...................................................................................8
       K. Comfort Conditions ..............................................................................................................8
   3.3 Supplier Specification .............................................................................................................8
4.     The Qualification of Air Handling Systems .........................................................................10
   4.1 Documentation......................................................................................................................10
   4.2 Design Qualification (DQ) .....................................................................................................10
   4.3 Risk Assessment ..................................................................................................................10
   4.4 Installation Qualification (IQ) ................................................................................................10
   4.5 Calibration plan.....................................................................................................................10
   4.7 Operational Qualification (OQ) .............................................................................................10
   4.8 Performance qualification (PQ) ............................................................................................11
   4.9 Requalification ......................................................................................................................11
   4.10 Technical Change Control ....................................................................................................11
5.     Preventative Maintenance.....................................................................................................11
6.     Monitoring...............................................................................................................................12
7.     Failure Plan.............................................................................................................................12
8.     Summary.................................................................................................................................13
9.     References..............................................................................................................................14
   9.1 References for Filters ...........................................................................................................14
   9.2 Reference for Particulate Level Control................................................................................14
   9.3 Reference of Summary Requirements for Each Type of Pharma Processing Area ............14
   9.4 Reference for Supporting Information ..................................................................................14
Appendices.......................................................................................................................................14
     Appendix I: Clean Room Recovery Rates......................................................................................................15
     Appendix IIa: Examples for air handling concepts - AHU for Solids with returning air ...................................16
     Appendix IIb: Examples for air handling concepts - AHU for Solids,100% fresh air.......................................17
     Appendix IIc: Examples for air handling concepts - Decentralized Dedusting ...............................................18
     Appendix III: Classification of Class of Areas.................................................................................................19
     Appendix IV: Comparison of Filter Efficiencies. .............................................................................................20
     Appendix V: ISO 14644-1 Particulate Standard .............................................................................................21
     Appendix VI: AIR-HANDLING (min. requirement)..........................................................................................22
     Appendix VII: Clean Room Manufacture- Particulate Standards....................................................................23
     Appendix VIII: Clean Room Manufacture - Microbiological Standards...........................................................24




Q-013                                                            Page 2 of 24                                                                     Version 2
1. Introduction and Objective

  This document provides the Merck Group guidelines regarding air-handling requirements
  necessary for the manufacture of Pharma Products.

  The two fundamental design and operation essentials of an “Air Handling System for
  Pharma Processing” are;

  •   Provide the correct environment for any “ Pharma Process Step”, by controlling
      temperature, air distribution and humidity, where necessary.
  •   Minimize the risk of airborne contamination and cross contamination by filtration,
      barrier technology, and appropriate pressure differentials.

  No area of “Pharma Production” can be in operation without proper controls for air
  handling. It is therefore essential to ensure that such systems are designed correctly,
  work correctly and are adequately maintained. Failure to implement or control air
  systems can have serious deleterious effects on the product produced. As a
  consequence the design and maintenance of air handling systems should be a visible
  and identifiable part of the “Company’s Quality System”. Pharma production
  encompasses a large number of operations. The basic design criteria standards for air
  handling can be classified according to the type of product manufactured as follows e.g.:

  •   Solid Dosage Forms

  •   Sterile Products

  •   Semi Solids

  •   Non Sterile Liquids

  This guideline is intended to:
  • outline the parameters that should be considered in the design of air handling
     systems
  • recommend minimum standards for the design parameters
  • identify key documentation requirements for air handling systems
  • outline the minimum requirements for qualification and calibration of air handling
     systems
  • outline minimum requirements for maintenance of air handling systems
  • recommend a minimum standard for monitoring

  The key elements to implementation and control of any air handling system are:
  • Zone Concept (Definition of clean room class and arrangement of the rooms)
  • Airflow regimens e.g.: air change rate, level of recirculation, room-pressure levels etc.
  • Definition of filter class
  • Temperature
  • Humidity
  • Monitoring concept
  • Particulate and bioburden levels

  All these parameters must be considered in the overall design of the system.


  Q-013                                Page 3 of 24                                  Version 2
  Any finished design should be based on a “User Requirement Specification”,
  approved as part of the “Company’s Quality System”. Such a specification should
  describe the operational settings for specific functions.

  The “Operational Maintenance and Control Programme” for any air handling system
  should be run in such a manner that the user requirement specification is met during
  operation. This maintenance and control programme must be incorporated into the
  “Company’s Quality System” as it is essential that there is an acceptable environment
  in which Pharma Production can take place.

  An “Action Plan” for any Critical Failure of an air handling system should be
  incorporated into the “Company’s Quality System”.

  The guideline is divided into six sections:

     •    Zone Concept
     •    Design of Air Handling Systems
     •    Qualification (including risk analysis and calibration)
     •    Maintenance
     •    Monitoring
     •    Failure Plan


2. Zone Concept

  The zone concept is determined through the basic layout of the production area
  according to the type of finished product, material and personnel flow, manufacturing
  process, equipment to define the clean room classes and the pressure cascade.
  Responsible for the zone concept is the process owner.
  It is important to design the airflows to ensure that air is contained in contaminated areas
  and is prevented from ingression into other areas by a system of area segregation. Areas
  of different classification of air cleanliness must be separated and where the areas
  interface, adequate pressure differentials must be maintained across the interface. The
  layout of an area should be designed for to minimize the risk of contamination of a clean
  area by another area.




  Q-013                                 Page 4 of 24                                  Version 2
3. The Design of the System

  The goal is to establish the minimum requirements and to fix or determine common
  standards with regard to design of air handling systems.
  Standards for air handling are being continuously upgraded, and as a consequence it is
  not considered necessary for older handling systems to immediately be upgraded to
  meet these standards. A risk assessment is advised for existing facilities to establish the
  need for an upgrade.

  Examples for technical concepts see Appendix II. For Filter Efficiencies and Particulate
  Standard see Appendix IV and V.


  3.1 User Requirement Specification (URS)

       It is important to accurately review and define the requirements of an air handling
       system for “Pharma Processing” prior to its design. Such a review should be fully
       documented as a record of the criteria for the design. This document known as
       “User Requirement Specification” is the foundation plan for any air handling system
       and should be the primary reference for the implementation of an air handling
       system for “Pharma Processing Areas”.

       It will often be the case that such a “URS” will not be available for an existing air
       handling system. It should be possible, however, to develop a retrospective “URS”
       for existing systems by reviewing the actual installed system in a similar way to a
       new system. This exercise in addition to a risk assessment is of importance as it is
       considered to be a useful tool in assessing if an upgrade is necessary to bring an
       existing system to current standards.

       The design items recommended for inclusion in any “User Requirement
       Specification” are outlined below.

  3.2 Factors to be considered in Design

       A. Quality of the Intake Air
       It is important to survey the potential risks of airborne contamination that could be
       drawn into the plant because of the location of the buildings in respect of the local
       environment (e.g. industrial area, agricultural area etc.). For example to consider
       the inlet air position in respect of exhaust air outlets from other buildings, and the
       consequent level of prefiltration required.

       B. The Prevailing Wind
       It is important when designing an air handling system to identify the prevailing wind
       to ensure that the inlet and exhaust ducts are located in such a manner that there is
       little risk of exhaust air being drawn into the inlet for this or any other exhaust duct.

       C. Climatic Conditions
       The climatic conditions in which the plant is located has to be considered. This will
       be necessary to determine the level of heating and cooling required as well as the
       percentage of recirculated air to fresh air for such a plant, and to identify whether
       dehumidification or rehumidification would be required. If it is established that
       rehumidification is a requirement, then the quality of the moisture injected into the

  Q-013                                Page 5 of 24                                     Version 2
    inlet air supply should be defined, taking into consideration inherent microbiological
    risk.

    D. Overall Design of the Air Handling System
    The concept behind the air handling design should be defined:

        •   Adequate pharmaceutical design (hygiene, materials, sealed ductwork etc.)
        •   Energy consumption efficiency (level of recirculation, filter classes etc.)
        •   Requirements for an optimized maintenance concept (running costs etc.)
        •   Electrical back up
        •   Impact of fire safety systems

    E. Product Specific Requirements
    A schematic for the pharmaceutical process should be outlined and the internal
    environment required should be defined.

    Environmental parameters that require definition will include temperature, humidity
    and level of filtration of the air entering and leaving the processing area both for
    process equipment and room.

    In order to minimize the risk of serious medical hazard due to cross contamination,
    dedicated and self-contained facilities must be available for the production of
    particular medicinal products, such as highly sensitizing materials (e.g. penicillin) or
    biological preparations (e.g. from live micro organisms). The production of certain
    additional products, such as certain antibiotics, certain hormones, certain cytotoxics,
    certain highly active drugs and non-medicinal products should not be conducted in
    the same facilities. For those products, in exceptional cases, the principle of
    campaign working in the same facilities can be accepted provided that specific
    precautions are taken and the necessary validations are made. The manufacture of
    technical poisons, such as pesticides and herbicides, should not be allowed in
    premises used for the manufacture of medicinal products.

    F. Air Flow Regimens
    The following needs to be considered:

    •   The level of pressure differential to ensure that an opening from another area
        will not contaminate the cleanest area
    •   The type of door openings and location of air locks to maintain the pressure
        differential and hence the segregation of areas

    Sterile processing (classified A-D areas):

    To maintain air quality in areas of higher cleanliness, it is important to achieve a
    proper airflow and a positive pressure differential relative to adjacent less clean
    areas. Rooms of higher air cleanliness should have a predefined positive pressure
    differential relative to adjacent rooms of lower air cleanliness. For example, a
    positive pressure differential of 12,5 Pa or higher should be maintained at the
    interface between classified and unclassified areas. The minimum requirement to
    meet current European Standards would be 10 Pa. A control tolerance of +/-3Pa is
    just respected. The effect of door opening and air leakage through doors should
    also be considered and minimized. The number of air changes in classified rooms


Q-013                               Page 6 of 24                                   Version 2
    to ensure that the “clean room” can recover adequately from a contamination should
    be defined. Clean room recovery rates are provided in Appendix I.

    Semi Solid or Non Sterile Liquid Manufacturing

    In case of manufacturing of semi solids (creams and ointments) and non-sterile
    liquids a positive pressure in rooms of higher air cleanliness is also recommended.

    Solid Dosage Form Manufacturing

    In multi-product solids manufacturing areas (e.g. tablet manufacturing site) the
    layout normally consists of a corridor with production cubicles located on each side
    of it. Different products are likely to be manufactured in each cubicle, and care
    should be taken that dust cannot move from one cubicle to another.

    The primary tool for cross-contamination control is correct directional air movement,
    which may be brought about a pressure cascade system.

    The corridor should be maintained at a higher pressure than the cubicles and the
    cubicles at a higher pressure than atmospheric pressure. There are, however, some
    instances where cubicles or processes should be maintained at a negative pressure
    relative to atmosphere, in order to contain hazardous substances, such as
    penicillines or hormones, etc.).

    Pressure differential and airflow rates should be sufficient magnitude to prevent of
    flow reversal concept.

    G. Air Change Rates
    The following should be evaluated to realise the optimal air change rate:

        •   Volume of the room
        •   Existence of deduster
        •   Generation of heat
        •   Formation of dust
        •   Development of humidity through the process
        •   Number of employees
        •   Necessary air flow
        •   Necessary air changes

    Airflow rates in solid and non-sterile liquid manufacturing should be above 5 1/h. The
    good engineering practice shows that airflow of 10 1/h is sufficient. Although higher
    airflow rates may be needed respecting the above numeration.

    H. Filtration
    It should be prefered to use a single pass system (100% of fresh air ). In case it is
    not possible to use a single pass system, because of climatic conditions,
    recirculation is permitted with HEPA filtered return air and monitoring of such a
    return filter. For the packing of closed products a recirculation with an F9-Filter for
    the return air would be adequate.




Q-013                               Page 7 of 24                                     Version 2
    I. Localised Area Design
    It is important not only to ensure correct flow in and out of an area, but to ensure
    that there is an adequate air flow in a particular area, and over a particular piece of
    equipment. This analysis of airflow does not only apply to “Pharma Processing
    Areas”, but also to areas for the entry of both personnel and materials into the
    processing area.

    Air regimens in an area, and the consequent location of air supply and extract
    should be detailed in respect of the room layout, and the setting of particular pieces
    of equipment. Room layout drawings should include the locations of equipment in
    the room to determine the optimum position for the inlet and outlet ducts.

    The location of the air supply and extract ducts in any area should be positioned to
    ensure that there are no “dead spots” in the room (an area in the room with
    insufficient air circulation).

    J. At Rest and in Operation Conditions
    There will always be a difference in the particulate concentration of an area at rest
    and in operation state. Particles will be generated from the product, personnel and
    equipment in use. Any air handling system should be designed to achieve the
    required conditions both at rest and in operation for clean manufacture.

    K. Comfort Conditions
    The environment must be suitable for the personnel working in the manufacturing
    areas. Factors to be considered in design to ensure “comfort conditions” for
    personnel will include zoning, type of clean room clothes, temperature, humidity, air
    velocity, heat gain, and heat loss.
    See Appendix VI.

3.3 Supplier Specification

    A detailed supplier specification (in most cases identically to the technical
    documentation delivered by the supplier) should be available and refer to the user
    requirement for any air handling systems used in “Pharma Production”.

    The technical documentation should include,

        •   Airflow schematic of the whole air handling system including process air
            handling equipment
        •   Pressure flow schematic to define the air flows direction in the processing
            areas
        •   The supply and exhaust velocity in the main air ducts of any fans both
            working and standby
        •   For HEPA Filters the air flow velocity at each supply and extract grill in the
            facility, with defined tolerances
        •   The levels of filtration within the design
        •   The temperature and humidity range in the area, if appropriate
        •   The pressure differential between zones
        •   The airflow rate at the outlets in the rooms and the number of air changes in
            each area/ processing room
        •   The mechanism for heating and cooling the air handling system, and the
            capacities of each system

Q-013                               Page 8 of 24                                    Version 2
        •   The mechanism design and control system for humidification or
            dehumidification
        •   The control mechanisms for failures of the main supply or extract systems
        •   Where necessary room schematics to demonstrate the airflow in a
            processing room
        •   Consideration for the ease of service access for maintenance, preferably
            from outside the GMP zone
        •   Airflow pattern studies

    The supplier specification can be largely addressed by a schematic in the form of a
    P+I diagram (piping and instrumentation diagram).

    For existing AHU (air handling unit) the retrospective URS and a risk assessment
    will lead to demands for completion of the available supplier specification.




Q-013                             Page 9 of 24                                  Version 2
4. The Qualification of Air Handling Systems

  4.1 Documentation
      A detailed scheme of testing is required to qualify the system against the URS.
      The document for all qualification work should include as follows:

          •   A protocol to outline the scope and extent of the qualification. Worksheets to
              record the values obtained against the user requirement specification with an
              indication of pass/fail on the sheets, and indication of readjustments if they
              were necessary
          •   The worksheets should reference both the operating procedures for the test
              and the reference for the instrument
          •   Where calibrated equipment is used, a calibration certificate against
              standards that are traceable to known International Reference Standards for
              the instrument, would be required
          •   A report and conclusion on the results of the qualification

  4.2 Design Qualification (DQ)
      Documented review of the user requirements and the supplier specification.

  4.3 Risk Assessment
      A formal risk assessment is the documented systematic use of information to
      identify specific sources of harm and to estimate the risk. The objective is to reduce
      potential risks by qualification of the air handling system. The risk assessment
      should be performed for each room.

  4.4 Installation Qualification (IQ)
      A new system or upgrade to a system will require formal installation qualification in
      accordance to the reference guideline Q-004 – Installation Qualification.

       The installation qualification will be related to the air handling equipment. Examples
       of such equipment include ductwork, fans, filters, grilles etc. When setting standards
       for equipment, it is important, where possible, to reference the tests to
       predetermined national or international standards. For example ductwork leakage,
       filter installation, monitoring equipment, etc., so that these pieces of equipment can
       be calibrated or tested against known and defined standards. The IQ can be based
       on the schematic of the air handling system.

  4.5 Calibration plan
      Equipment that is critical for assuring the quality of the room conditions should be
      calibrated according to written procedures and an established schedule.

  4.7 Operational Qualification (OQ)
      A new system or an upgrade to a system will require formal operational qualification
      in accordance to the reference guideline Q-005 – Operational Qualification.

       The operational qualification will relate to:

          •   The balancing of the pressure differences so that the area meets its original
              design specification, both in terms of airflow through the main ducts and the
              volumes delivered to every inlet and exhaust grill
          •   The airflow pattern should be confirmed in critical areas

  Q-013                                Page 10 of 24                                 Version 2
           •   The filter leakage and blockage and its relation to pressure differential across
               the filter should be established for each filter system used to supply air to
               “Pharma Processing” areas. This data should be used to define a working
               range for pressure differentials to ensure that the filters are working
               efficiently. A filter integrity test is required for HEPA filters

        In addition other tests to be considered during OQ include:

           •   Air flow visualisation: using aerosol made from water for injection generated
               to confirm the absence of dead spots in localised area such as in the vicinity
               of equipment in an area. These smoke studies should be video recorded and
               be part of the OQ documentation for sterile areas
           •   Recovery time: to determine the clearance rate of a particulate loading, see
               Appendix I for theoretical clearance (class A-D)
           •   Containment Leak Test (search of leakage of the clean room) according to
               ISO 14644-3:-, chapter B.14

  4.8     Performance qualification (PQ)

        For areas classified as class A-D, monitoring particulate levels and the
        microbiological status in a processing area should prove the efficiency of filtration.
        The particulate levels should be in compliance with EU/ISO standards. The
        microbiological status should comply with EP or USP. Further details of the extent
        of the work to classify an area to ISO standards is outlined in Appendix III and VI.

  4.9 Requalification

        All air handling systems in “Pharma Processing” should undergo a formal
        requalification on a regular and defined basis due to the calibration plan. Any
        requalification must be documented and formally approved before and after the
        work as part of the overall Company’s Quality System.

        This requalification will be similar in nature to the original qualification, but a
        reduced programme would be accepted provided that it can be demonstrated that
        the overall qualification programme proves that the air handling system is
        performing to its design specification.

  4.10 Technical Change Control

        Air handling systems are subject to upgrade and change. It is important to control
        any change through a change control system in the design specification. Any
        change should be traceable to the original design specification.

5. Preventative Maintenance
  Schedules and procedures (including assignment of responsibility) should be established
  for the preventative maintenance of equipment.
  Factors that should be considered to ensure that the air handling system is operating in
  compliance with specification are:
        • Room/Area pressure differentials
        • Filter differentials for supply and where necessary return from an area.
        • Particle levels in “clean areas”
        • Cooling coils and humidifiers should be checked for cleanliness and drainability

  Q-013                                Page 11 of 24                                    Version 2
       •   Cleanliness of supply & return air in ducts and coils, check for corrosion on coils,
           humidification & dehumidification systems
       •   Review of any modifications and the upgrade of documents

  A logbook should be maintained to ensure that there is an accurate record of the “history”
  of the system. The record in the logbook must not only log routine measures but also
  indicate where and when qualification, breakdown, requalification, filter changes etc.
  have taken place.

6. Monitoring

  Routine checks should be carried out in all processing rooms to ensure that the air
  handling system is performing within its stated specification during any pharmaceutical
  processing. The level of monitoring will be dependent on the area of use. Obviously a
  high-grade area would require a higher level of scrutiny than a lower level. For any
  processing area a justification for the level of testing to ensure compliance with the
  specification of any air handling system would be expected.

  For Class A-D areas particulate monitoring should be performed in accordance to ISO
  (see Appendix III and VI).

  It is recommended that continuous monitoring of particulate contamination be employed
  in critical areas where sterile products are manufactured where this is technically
  feasible. Particulate monitoring data should be reviewed against the design specification
  at regular intervals.

  Factors that should be considered to ensure that the air handling system is operating in
  compliance with specification are:

       •   Room/Area pressure differentials
       •   Particulate levels in “clean areas”
       •   Temperature & humidity
       •   Bioburden levels

  The recommended temperature ranges should be depending on the location of the
  factory and product requirement based on stability information. It should be noted that
  where air systems are not capable of controlling the temperature/humidity within the
  specified range, an action programme is required.

  Any check on the parameters used for ensuring correct operation of an air handling
  system, such as temperature, humidity, pressure differentials, particulate levels,
  microbiological data should be duly recorded in a “log book” or related document system.
  Each parameter should be checked to ensure that it is within its “working range”. Any out
  of range recording should be documented and the actions as a consequence of such an
  out of range result should be formally documented according to written procedures.
  It is recommended that a competent person should independently review the monitoring
  record at predefined intervals.

7. Failure Plan

  Air handling system can fail to deliver air of the correct quality and quantity to an area. It
  is usual to design the air handling system in such a way to minimize the effect of failure

   Q-013                                Page 12 of 24                                    Version 2
  of a component of the air handling system, by including such items as stand by motors
  etc.
  It is recommended to establish a “ Failure Plan”, where possible failures are identified. An
  action plan is required to ensure that any product exposed is protected.

  It should be considered that in cases of a deleteriously affection of the product by a
  failure a rejection might be necessary.


8. Summary

  This guideline recommends a series of core elements to ensure proper design and
  operation of an air handling system “for Pharma Processing”.

  The key elements are,

     •    Zone concept
     •    User requirement specification
     •    Supplier Specification
     •    Risk assessment
     •    Design Qualification
     •    A Detailed Initial Qualification Protocol & Report for IQ, OQ, PQ
     •    Requalification against the URS as a formal process of testing and review
     •    A formal review of operating results collected during preventative maintenance for
          the air handling systems against a known working range
     •    A logbook to provide a historical record of the operation of the system
     •    A monitoring system for all relevant parameters
     •    An action plan in the event of failure




  Q-013                               Page 13 of 24                                   Version 2
9. References

9.1 References for Filters

    CEN (EN 779, EN 1822) with classification of filters G 1 to G 4. F5 to F 9, and H 10
    to H 14, standards for classification of filters are used in this guideline.
    For example an HEPA is classified as H13, 14 and is recommended for all areas
    classified classes A - C, F9 is of sufficient filter efficiency to achieve a Class D
    environment. It is recommended that F9 be used for non-sterile processing areas,
    where active pharmaceutical ingredients are exposed.

    A comparison of ASHRAE EU and EN filtration efficiencies are provided in
    Appendix IV.

9.2 Reference for Particulate Level Control

    The EU & US standards are in the process of harmonisation, that is why CEN had
    adopted in May 1999 a new ISO standard: ”ISO 14644-1: 1999". ISO and TC 209
    had prepared this ISO standard in collaboration with CEN and TC 243.

9.3 Reference of Summary Requirements for Each Type of Pharma Processing
    Area

    For ease of reference a summary table has been included in Appendices VI - VIII to
    indicate the minimum standards for each type of manufacture,

9.4 Reference for Supporting Information

    USP 28 Chapter 1116.
    ISO 13408 Sterilisation of healthcare products- aseptic products-Part 1 General
    requirements.
    VDMA 24186 part 1-3- Clean room technology.
    Programme of services for the maintenance of air handling and other technical
    equipment in buildings Part 1
    DIN EN ISO 14644-1 Classification of air cleanliness
    DIN EN ISO 14644-2 Specifications for testing and monitoring to prove continued
    compliance with ISO 14644-1
    DIN EN ISO 14644-3
    DIN EN ISO 14644-4 Design, construction and start up
    ISO 14698-1 clean rooms control of bio contamination 2003
    ISO 14698-2 –evaluation and interpretation of results of bio contamination
    EC GMP Guide
    FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing –
    Current Good Manufacturing Practice, September 2004
    WHO Working Document QAS/02.048 Rev.1, Supplementary guidelines on good
    manufacturing practices for heating, ventilation and air-conditioning systems for
    non-sterile dosage forms


Appendices



Q-013                             Page 14 of 24                                  Version 2
                                     Appendix I: Clean Room Recovery Rates




               7                                              C = (C c) (s) exp( Nt) + Cs*
             10                                               where c = final room concentration
                                                                     Co = initial room concentration
                                                                     Cs = supply air concentration
             10
               6                                                     N = room air change rate           Class 100000
                                                                     t = time (hours)
  Particle
Concentration 5
             10
 (log scale)
                                                                        10 air changes per              Class 10000
                                                                        hour
               4
             10


               3                                      20 air changes
             10                                       per hour
                      30 air changes per
                      hour
               2                                                                                        Class 100
             10



               1
             10        40 air changes per
                       hour
                                                                                                                       Time (minutes)

*Assuming perfect air mixing    10          20   30            40                50                60




     Q-013                                            Page 15 of 24                                                                 Version 2
Appendix IIa: Examples for air handling concepts - AHU for Solids with returning air



                                         motor with
                                         frequency                                          PIC
               F7                                                                F9 HEPA
                                         inverter
   fresh air

                                                                   -   +




  exhaust
                    F9      F7                        TIC              air flow regulator



                                              air flow rate >5 1/h


                                               process room




     Q-013                                         Page 16 of 24                                  Version 2
Appendix IIb: Examples for air handling concepts - AHU for Solids,100% fresh air



                                                          motor with
                                                          frequency
                                                          inverter
                                                                                                   PIC
                                                     F7                                       F9
                                           100%
                                         fresh air
   motor with
   frequency                                                                   -   +
   inverter                        PIC




   exhaust
                         F9   F7                                       TIC         air flow


                                                            air flow rate >5 1/h


                                                             process room




     Q-013                                           Page 17 of 24                                       Version 2
Appendix IIc: Examples for air handling concepts - Decentralized Dedusting




              air flow regulator




     Air                                                                  conditioned




      technical area               tablet press room                   corridor




     Q-013                                             Page 18 of 24                    Version 2
                     Appendix III: Classification of Areas
               Classification of Areas by the level of Particle Contamination.

It is necessary to classify a “clean “ area for manufacture formally as part of the validation
process at least annually.

To classify it is necessary to define number of locations to certify area.


According to EN ISO 14644-1:1999 the minimum number of locations (NL) is calculated as
follows:


Minimum number of locations (rounded to an integer) (NL) = √A

Where A = area of room in m2


To classify need to define the minimum number of particles that are to be detected.

By the very nature of the test, the procedure should be designed to ensure that particles are
detected; a zero reading will not necessarily mean that the area is acceptable.

“Each sample of air tested at each location shall be of sufficient volume such that at least 20
particles would be detected if the particle concentration were at its class limit for the specified
particle size.

Therefore Vs= (20/ Cn,m) x 1000.

Vs is the minimum single sample volume per location, expressed in litres.

Cn,m is the class limit (number of particles /m3) for the largest considered particle size
specified in the relevant class.

20 is the defined number of particles that could be counted if the particle size concentration was
at the class limit.

For class A and B areas the sample volume should be 1m3

What Acceptance Criteria can be applied to comply with particulate standards?

To pass a specification if more than ten readings are taken then the average of all data taken has
to be below the specified limit
If below 10 readings, there has to be a 95% confidence that the particle size limit will be met.




Q-013                                    Page 19 of 24                                        Version 2
                                 Appendix IV: Comparison of Filter Efficiencies.




                                                                                    Arrestance
                                 EN 1822                      (Cancelled norm)                     Dust Spot
                                 EN 779                       Eurovent Class -                     Efficiency    Sodium Flame
                               CEN/TC/195                     Eurovent 4/5 (2-9)                 ASHRAE 52/76      efficiency
                                WGI-GI-F9                     Eurovent 4/9 (2-9)                 BS6540 Part 1    Eurovent 4/4
                               WG2-H10-U16                   Eurovent 4/4 (10-14)                    (1985)      BS3928 (1985)
                                                                                    %                   %               %
                              Total value for MPPS
                              Min separation rate %
                          U17      99,999995
 ULPA




                          U16       99,99995
                          U15        99,9995                                                                       99,99995
                          H14           99,995                       EU14                                           99,9995
                          H13            99,95                       EU13                                           99,999
 HEPA




                                                                     EU12                                            99,99
                          H12            99,5                        EU11                                            99,97
                          H11             95                         EU10                                             99,9
                          H10             85                                                                           95
                          F9            95≤Em                        EU9                              95              85
                          F8          90≤Em<95                       EU8                              90              75
                          F7          80≤Em<90                       EU7                              85
                                                                                                      80
 Fine dust filtration




                                                                                                      75
                          F6          60≤Em<80                       EU6                              70
                                                                                                      65
                                                                                                      60
                                                                                                      55
                          F5          40≤Em<60                       EU5                              50
                                                                                                      45
                                                                                                      40
                                                                                                      35
                          G4            95≤Am                        EU4            95                30
 Coarse dust filtration




                                                                                    90                25
                          G3          80≤Am<90                       EU3            85                20
                                                                                    80
                                                                                    75
                          G2          65≤Am<80                       EU2            70
                                                                                    65
                          G1            Am<65                        EU1


ULPA                      Ultra low penetration air (filter)
HEPA                      High efficiency particulate air (filter)
MPPS                      Most penetrating particle size
Em                        Mean efficiency rate
Am                        Mean separation rate




Q-013                                                           Page 20 of 24                                          Version 2
                Appendix V: ISO 14644-1 Particulate Standard

Selected ISO 14644-1 airborne particulate cleanliness classes for cleanrooms and
clean zones.

 Classificati     Maximum concentration limits (particles/m3 of air) for particles equal to and
 on                                           larger than the
                    0.1μm          0.2μm          0.3μm           0.5μm           1μm           5.0μm
      ISO1            10              2
      ISO 2          100             24             10              4
      ISO3          1000            237             102             35              8
      ISO4          10000           2370           1020            352             83
      ISO5         100000          23700          10200           3520            832             29
      ISO6        1000000         237000          102000          35200           8320            293
      ISO7                                                       352000          83200           2930
      ISO8                                                      3520000         832000          29300
      ISO9                                                      35200000        8320000         293000

ISO =   International standard. It specifies the log10 of particles with 0.1μm at rest (I.e. ISO 5 = 100,000
        particle/m3 of air). It can be calculated for any particle size of interest by the following formula:
Cn = 10N{0.1/D}2.08
Cn      represents the maximum permitted particle concentration (particles/m3) of airborne particles that
        are ≥ the selected particle size
N       represents the ISO classification up to a maximum of 9.
D       represents the particle size to be considered
0.1     is a constant of 0.1μm.




Q-013                                       Page 21 of 24                                               Version 2
                                                    Appendix VI: AIR-HANDLING (min. requirement)

            Activities                     Filter         Temperature          Humidity                Pressure               Air changes           Qualification DQ-PQ
                                                              ****                                                               per hour
  A Steriles (sterile zone,                HEPA          15-25oC (30°C)          <80%                     pos.               flow of 0.3 m/s       yes, Filter Integrity Test,
  laminar flow)                            (H 14)                                                                           (vertical) or 0.45     CFU, Particle Counting
                                                                                                                             m/s (horizontal)
                                                                                                                                with ± 20%
  B (sterile zone)                         HEPA          15-25oC (30°C)          <80%                     pos.                      >30            yes, Filter Integrity Test,
                                           (H 14)                                                                                                  CFU, Particle Counting
  C (clean zone)                           HEPA          15-25oC (30°C)          <80%                     pos.                    >30              yes, Filter Integrity Test,
                                           (H 14)                                                                                                  CFU, Particle Counting
  D (clean zone)                            F9           15-25oC (30°C)          <80%                     pos.                    >10            yes, CFU , Particle Counting
  E Semisolids Ointments,                  F 9 **        15-25oC (30°C)          <80%                     pos.                    >5                       yes, CFU
  Creams, Oral Liquids,                                                                          air flow from primary
  Aerosols                                                                                      packaging to secondary
  (incl. primary packaging)                                                                           packaging ***
  F Solids (incl. primary                  F 9 **        15-25oC (30°C)         <80%*                     neg.                      >5                     yes, CFU
  packaging)                                                                                     air flow from primary       (+ if particles
                                                                                                packaging to secondary         emission)
                                                                                                        packaging
  Packing closed products              F 5 (F 7)*****    15-25oC (30°C)          <80%                    no. req.                  >5                         yes

* Effervescent tablets require in most cases relative humidity of < 30%
** The levels of filtration specified in the tables apply to both process air and room air.
*** Protect semi-solid, oral liquids and aerosol filling, where product is exposed, with laminar flow.
**** Changes to these recommended temperature ranges up to 30°C are possible, but should be based on product stability data.
***** in most cases a F7 filter, if necessary with a prefilter F5, will be appropriate.

CFU:                          Colony forming unit
Filter Integrity Test:        ISO 14644 recommended aerosols: DEHS (bis(2-ethylhexyl)-sebacat), DOP (dioctyl(2-ethyl-hexyl)phthalate), PAO (poly-alpha-olefin) or
                              equivalent aerosols like PSL (polystyrol-latex) etc. In some countries DOP is not recommended by the local authorities regarding safety
                              reasons. The FDA Guide “Sterile Drug Products Produced by Aseptic Processing” mentions DOP and PAO as examples for appropriate
                              aerosols. However any aerosol used should not promote microbiological growth.




Q-013                                                                       Seite 22 von 24                                                                 Version 2
                                   Appendix VII: Clean Room Manufacture- Particulate Standards

         Grade                             Maximum Permitted Particles/m3                                                      Comments
                                     at rest                         in operation
                             ≥0.5 μm          ≥5 μm          ≥0.5 μm              ≥5 μm
           A                  3,500             0*            3,500                 0*            Unidirectional laminar flow with terminal HEPA filters. Apply this
                                                                                                  locally where sterile products are exposed.
                                                                                                  Continuous monitoring of particle count and microbiological count
                                                                                                  in area during manufacture.
           B                  3,500               0*              350,000            2,000        Turbulent Flow room supply with terminal HEPA filters.
                                                                                                  Continuous monitoring of particle count and microbiological count
                                                                                                  in area during manufacture
           C                 350,000             2,000          3,500,000           20,000        Turbulent Flow room supply with terminal HEPA filters.
           D                3,500,000           20,000          not defined       not defined     Turbulent Flow with F9 filters in main duct.


Grade A, B, C and D according to Annex 1 of the EC Guide to Good Manufacturing Practice
* Annex 1 is under revision; limits should be adopted according to new version of Annex 1
At rest =       when there is no manufacturing or personnel in the area, i.e. 15 to 20 minutes after operation have ceased in an area
In operation = during manufacture with a specified number of personnel working.
HEPA =          H10 – H14




Q-013                                                                    Seite 23 von 24                                                              Version 2
                             Appendix VIII: Clean Room Manufacture - Microbiological Standards

        Activities       Microbio       Microbio       Microbio       Microbio
                          cfu/m³      Settle plates     Contact      Glove print
                       in operation    cfu/4 hours       plates       5 fingers
                                      in operation    cfu/plate in   cfu/glove in
                                                       operation      operation
  Steriles A (lam.         <1             <1               <1             <1
  flow)
  B (sterile zone)          <10             <5            <5             <5
  C (clean zone)           <100            <50            <25          no. req.
                          (<10**)         (<5**)
  D (clean zone)           <200            <100           <50          no. req.
                         (<100**)        (<50**)
  Semisolids E            <1000*          <500*         no. req.       no. req.
  (Ointments,
  Creams)
  Oral Liquids
  Aerosols
  F Solids               <1000*          <500*          no. req.       no. req.
  Packing closed         no. req.       no. req.        no. req.       no. req.
  products

* Internal specification used at Merck Darmstadt, which is proposed for the guideline.
** US FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004




Q-013                                                                Seite 24 von 24                                                          Version 2

				
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