Document Sample
					                                                        Appendix 2.B


                       ITB Number: 15003349


          For the replacement of equipment at Altayvitaminy

                   Project Number: GF/RUS/12/003

Phase out of CFC consumption in the manufacture of aerosol metered-
           dose inhalers (MDIs) in the Russian Federation

ITB No. 15003349                                              Page 1
Project Objective

The objectives of this project are to phase-out the consumption of 212 ODP tonnes of
CFC-11 and CFC-12 used in the manufacture of Aerosol Metered-Dose Inhalers (MDIs)
in the Russian Federation (RF) and to reduce future GHG emissions by approx. 1.7 MMT
CO2 t/equivalent, by introducing a new propellant with lower Global Warming Potential
(GWP). This Terms of Reference addresses the requirements for conversion of a
manufacturing facility currently using CFCs to manufacture MDIs with CFC-free

1.     Background Information

The Russian Federation as a legal successor of the former Soviet Union is a party to the
Vienna Convention for Protection of the Ozone Layer and to the Montreal Protocol on
Substances that Deplete the Ozone Layer (Montreal Protocol). In January 1992, Russia
ratified the London Amendment to the Montreal Protocol and in December 2005 it
ratified the Copenhagen, Montreal and Beijing Amendments to the Montreal Protocol.

Under the Montreal Protocol and London Amendment the Russian Federation was
obliged to phase-out the production of the controlled substances listed in the Annexes A
and B to the Montreal Protocol by 1 January 1996. In 1995 the Russian Federation
requested a delay in the fulfilment of its obligations under the Protocol. Significant
phase-out of CFCs and Halons started however, in December 2000.

As a non-article 5 country under the MP the Russian Federation was not eligible for
international assistance available under the Multilateral Fund of the Montreal Protocol
(MLF). As a consequence, the Global Environmental Facility (GEF) formally opened an
Ozone Focal Area in 1995 for CEITs, who had Country Programs endorsed by the Parties
to the MP and had ratified the London Amendment.

As a result of the implementation of the ODS phase out programme CFC production
ceased in 2000 in the Russian Federation and further import of Essential-Use CFCs only
for MDI production is being now regulated on the basis of the annual quota from the
Ministry of Natural Resources and Ecology (MNRE) or supplied from the stockpile.
Russia has been importing ODSs from China and India since 2003. In the last years the
import was only from China.

After 2005 only two enterprises continued to use CFCs for the production of MDIs. The
companies are Altayvitaminy Ltd., Altay region and “Federal State Enterprise N.A
Semashko” also known as MosChimPharmPreparaty, Moscow. Both have applied for
Essential Use Nomination (EUN) for CFCs in order to ensure the supply of
pharmaceutical-grade CFCs for the Aerosol Metered-Dose Inhaler (MDI) applications. A
final quota for the Russian Federation was approved by the Meeting of the Parties to the
Montreal Protocol (MOP) for the year 2012.

ITB No. 15003349                                                                Page 2
Decision XXI/4(8) of the MOP requested the Technology and Economic Assessment
Panel and its Medical Technical Options Committee to “organize and undertake a
mission of experts to examine the technical, economic and administrative issues affecting
the transition from CFC metered dose inhalers to CFC-free alternatives in the Russian
Federation. As a result of this mission TEAP recommended financial support through
GEF funding which should govern the success of the transition in the Russian Federation.
Based on the TEAP recommendations, the Parties to the MP could expect that within 18-
24 months the production lines could be converted completely.

In 2008, the Ministry of Health and Social Development through FSNS (Rossdravnadsor)
requested UNIDO to render technical assistance in developing an MDI project to phase
out the use of CFCs in MDI manufacture in the Russian Federation. In November 2011
the project to phase-out CFCs in the production of MDI was endorsed by the CEO of

In the following Terms of Reference for the product specifications to replace the use of
CFCs in the production of MDI at Altayvitaminy are set out.
Altaiskii krai, g.Biisk, Zavodska str. No.69
659325 Russian Federation

2.     Service Requirements

3.1.   One complete inhaler filling line with flame proof filling machine.

3.2.   Normative documents to be used as reference

1) The United States Food and Drug Administration (FDA), 21 CFR 210 - Current Good
Manufacturing Practice in manufacturing, processing, packing, or holding of drugs.
2) FDA, 21 CFR 211 - Current Good Manufacturing Practice for finished
pharmaceuticals; subpart D – Equipment.
3) FDA, 21 CFR 177 – Indirect food additives: polymers.
4) FDA, 21 CFR 178.3570 - Lubricants with incidental food contact.
5) FDA; 21 CFR 11 - Electronic records; electronic signatures.
6) GAMP 5, A Risk-Based Approach to Compliant GxP Computerized Systems.
7) EEC guide to Good Manufacturing Practice for medicinal products – III/2244/87-EN,
Rev. January 3, 1989 incl. additional regulations, specifically Section 5.21 and Appendix
8) Directive ЕС 2001/83/EC of the European Parliament and of the Council of November
6 2001 on the community code relating to medicinal products for human use.
9) The rules governing medicinal products in the European Union: Vol. 4 - Good
Manufacturing Practice guidelines, Annex 11 Computerized system.
10) FDA guidance for industry: Personnel, main principles of software legalization.

ITB No. 15003349                                                                 Page 3
11) FDA inspection guide for computer issues: Glossary of computer systems and
software development terminology.
12) PIC Principles of qualification and validation in pharmaceutical manufacture, PHG
13) PIC/S PR 1/99-1: Validation master plan, installation and operational qualification,
non-sterile process validation, cleaning validation.
14) PIC/S PR 1/99-2, Pharmaceutical inspection convention – References.
15) PIC/S Good Manufacturing Practice (GMP) Annex 11: Computerized systems.

3.3.   General product specification

Filling capacity:
               Product (Suspension) with Alcohol: 0,5 – 3,5 ml
               Propellant (HFA-134a): 1 – 20 ml
Canister size: 19ml (59.0mm x 22.0mm)
Canister type: Aluminium
Line capacity: 3600 canisters per hour (maximum)

3.4.   Machine functions

1) A complete automatic inhaler filling line to be offered.
2) A suitable conveyer should be included to integrate all the machinery.
3) The line should consist of the following machinery:

3.4.1. Can feeding system

      Cans are delivered in bulk. The canisters are to be loaded manually at machine in
       feed hopper. The sorter with reservoir is required to hold a sufficient number of
      A conveyor belt at the bottom transports the cans to an elevator. The reservoir can
       be emptied completely by running the conveyor belt backwards.
      Stage 1: The elevator raises the cans to the sorting bowl;
      Stage 2: Cans are moved inside the rotating sorting bowl;
      Stage 3: Cans exit the sorter bowl in a horizontal lying position;
      Stage 4: The cans then travel through an outlet turn to arrive at the feed conveyor
       of the can orienting unit;
      Machine base to be fabricated from stainless steel 304;
      Emergency stop button should be located within easy reach of the operator
      User friendly control panels to be mounted on the machine;
      The machine should have the following features:
      Variable speed control system;
      Canister low-level sensor;
      Easy change over system;

ITB No. 15003349                                                                   Page 4
      Guards with door and door switches;
      Access door to hopper for easy cleaning. Can cleaning system
       Horizontal lying cans – with can opening pointing forward or backward - are
        transported into the can orientation star wheel;
       Correct orientation of the cans, with can opening on top;
       Cleaning Station: The can is picked up by means of a vacuum suction cup and
        turned mechanically upside-down;
       Cleaning operation by suction bell around the can body and an air jet nozzle into
        can opening;
       Particles are blown off with an air blast cleaner and sucked away by vacuum
       Cans are turned back to open-side-up position
       Cleaning medium: air filtered to 0,1µm

3.4.2 Product filling machine

        Canisters to be fed automatically from the can cleaner through conveyor to the
filling machine;
        The Product Filler serves to fill solutions or suspensions into the open cans;
        The product is supplied to the metering unit via the inlet shut-off valve;
        The product then passes through the metering unit and down to the diaphragm
filling nozzle;
        The filling volume can be changed by a scale with micrometer screw;
        Machine should be oil free pneumatically controlled;
        All parts in contact with the product should be in SS 316L or Teflon material;
        All connections should be quick coupling type;
        The product filler should have quick change feature to permit a fast change to
other formats and products;
        Volume adjustment by metering unit;
        Filling capacity: 0,2 - 5.0 ml;
        The filling accuracy should be ± 0.02 g for 0.1-2 ml;
        The machine should have the following features:
             o Filling head without dynamic gasket - only diaphragm sealing system are
             o Filling head attached to metering unit - without flexible hose connection
                 between metering chamber and filling head;
             o The machine should be flame proof.

3.4.3. Valve handling system Valve sorter
       The valves to be loaded manually in the sorting machine;

ITB No. 15003349                                                                   Page 5
      Valves are sorted in the vibrating bowl where any incorrectly oriented valves are
guided off the bowl exit track;
      Vibration of the bowl for speed control to be adjustable by a potentiometer;
      Noise guard with in feed opening over vibrator;
      Valve minimum level alarm to be incorporated in the machine. Valve transport system
       The aerosol valves are transported from the sorter to the inserter by a rail system;
       A drive unit brings the valves up to a suitable height;
       Chain conveyor with chain stretching device and variable frequency gear drive;
       Telescope system to compensate for height changes (height change for sorter is
        not acceptable);
       Fully controlled by fibre optics;
       Double track system for different valve types. Valve insert device
       Valve to be placed on each canister after product filling;
       Valve Presence Control, situated after the Inserter, will stop the machine when no
        valve has been inserted;
       Detection of “no valves” or “no cans” will stop the machine.

3.4.4.   Automatic can crimping machine
        Cans to be fed automatically from the filling machine to the crimping machine;
        Oil free pneumatic control system;
        Crimping height and depth should be quickly adjustable with crimping head
         remaining at place;
        Machine should have the following parameters:
             o The contact pressure can be adapted pneumatically between 3 and 10 bar
             o Vacuum function (vacuum crimping) as an optional feature for different
                 product requirements;
             o Grip assembly of adjustable height for 14 – 19 ml cans.

3.4.5. Propellant (HFA) filling machine

        Automatic feeding of cans from crimping to propellant filling machine;
        Oil-free pneumatic filling machine;
        All product-contacting parts are made of stainless steel 316L;
        All connections should be quick coupling type;
        Volume adjustment by metering unit;
        Filling capacity: 0 – 20.0 ml;
        Filling accuracy should be ± 0.2 g;
        Module should have the following parameters:
             o Oil-free pneumatic control system;

ITB No. 15003349                                                                     Page 6
         o Filling head without dynamic gasket. Only diaphragm sealing systems are
         o Shut-off valves without dynamic gasket. Only diaphragm sealing systems
           are suitable;
         o Easy change over system;
         o “No can – no filling” system.

3.4.6. Weight checking machine

     Can feeding conveyor;
     Appropriate transport system feeding cans to weighing panel;
     Weighing should be carried out in fixed position without external influences (air
      flow or vibration);
     Weight accuracy < ± 5 mg;
     Rejection of under and overweight cans;
     Sorted cans should be collected into appropriate collection bin made of impact
      resistance robust plastic material;
     Alarm system for disqualified cans;
     Calibration system for the load cell;
     Suitable plexiglass cover;
     Maximum load senso;
     Control panel with touch screen to feature emergency stop button & alarm
      messages for fault finding; user friendly operation with password access for
      different levels and data backup facility;
     Balance certification package.

3.4.7. Manual unloading table

     Filled and crimped cans will come to this table through the conveyor and will be
      collected manually by an unloading tray.
     Table must be made of stainless steel 304.

3.4.8. Propellant pump

     The pump should be pneumatically operated;
     The pump should always maintain a constant pressure of 10 bar (max) at its
     Pharmaceutical grade analogue pressure sensor after the filter;
     Pump capacity: 15 l/min;
     Product contact part may be SS304 since there is a 0.22 micron filter after the
     Flame proof.

ITB No. 15003349                                                                 Page 7
3.4.9. SS lobe pump

      The suspension / solution is recirculated through the filling head back to the
       mixing vessel to ensure homogenous filling;
      Housing, shaft and rotors should be made of SS 316L;
      Variable speed;
      Pressure pump outlet: 4 bar (max);
      Capacity: 0.8 m3/h
      Connection type: quick coupling for filler and TC clamp for pump.

3.5.   Wearing spare parts

The supplier should provide wearing spare parts and electric/electronic spare parts for 2
years of usual 1-shift production.

4.     General characteristics

4.1.   Design type

The Equipment defined in this specification shall conform to:

      The current state of the art GMP;
      European Medicine Agency (EMA) and FDA regulations and guidelines, as may be
       applied to this type of equipment. See legal requirements.

In the design and construction of the equipment, the supplier shall separate technical parts
(motors, etc.) from pharmaceutical parts in direct contact with the product, as far as

Stainless steel must be welded under inert gas (argon or nitrogen) and the welds treated by
pickling and passivation, to prevent any subsequent corrosion. All welds should be crack
and crevice free. Internal welds and welds likely to be in contact with the product shall be
ground smooth and flush. All other welds to be ground smooth. All welds shall be polished
to the same standard as the surrounding areas.

Stainless steel fabrication areas should be totally segregated from any areas where carbon
steel machining, grinding or similar operations are carried out.

ITB No. 15003349                                                                    Page 8
4.2.   Materials used

All parts of the equipment in contact with the product shall be either stainless steel 316L
and polished or, as otherwise requested in the User Requirement Specification [URS]
(Article 1) of this Specification, or other materials compliant with FDA Regulations 21
CFR 177. (PTFE was found to be the preferred material). Surfaces that contact
components, in-process materials, or drug products shall not be reactive, additive, or
absorptive, so as to adversely affect product quality.

Product contact surfaces: internal filler Ra < 0.5 μm and internal valves & pipeworks Ra <
1.0 μm.

All product contact lubricants shall be food grade.

With the exclusion of certain ancillary items in the technical area, the use of materials
requiring painting to resist corrosion shall be avoided.

4.3.   Cleaning

The design and construction of the equipment shall be such that sharp angles and corners
and other parts, not easily accessible for cleaning are avoided.

4.4.   Format or product changes

In order to reduce the time taken for a format or product change, the supplier shall make
every effort to standardize the types of fixing for the change parts required for each format.

All the change-parts relative to a particular format shall be engraved with the same
reference, to aid identification.

The facility to change format parts with the use of tools and positive location of change
parts is preferred wherever practical.

4.5.   Effectiveness of Seals

For normal operation with the services defined in Article 4, there must be no escape of
product, water or other fluid. Note the requirements to avoid dynamic seals – diaphragm
sealing system are preferred.

In the case where some loss is inherent in the normal functioning of the equipment, this
loss should be contained in such a way as to prevent the escape of product etc. onto the
walls and floors of the production area.

ITB No. 15003349                                                                      Page 9
4.6.   Heat insulation

No part of the equipment should heat up to 55°C during usual production.
Parts potentially heating up to 55°С must be covered by mineral or chemical insulation
materials and bordered. Parts inside a pharmaceutical area should be surfaced with
stainless steel (AISI 304).

Note: No asbestos, in any form, shall be permitted for any purpose.

4.7.   Wiring requirements

All wiring should be furnished according to the latest edition of CENELEC/IEC

All electric equipment located in manufacturing areas should be classified according to
IP55 (dust and water protection) unless specified otherwise by user or located within the
machine, in sealed branch cases.

Electric equipment located outside technical manufacturing areas should have at least
IP41 qualification. All equipment should have operation time counter and designed to
interact with the entire line including emergency shutdown buttons.

Control device 4 – 20 mA for analog signals and 24Vdc - for digital ones.

5.     Supplier’s Responsibilities

      The supplier assures that all calculations, plans, assessments and other documents
       conform to normative documentation in item 3.2. Inspections carried out by
       Altayvitaminy should not exempt the supplier from this liability, wholly or in
      The supplier assures that the shipped equipment conforms to trade standards,
       factory standards including industrial safety standards and to applicable laws and

5.1.   Noise

      Noise level at workplace for each machine operating at maximal speed should not
       exceed 80 decibel (A) at the position of operator or at the distance of 1 meter from
       the machine. The supplier should declare the noise level during usual operation of
       the equipment.

ITB No. 15003349                                                                   Page
5.2.   Machine safety & protection of dangerous parts

      Machine protection should comply with requirement laid down in PD 5304:2005,
       Guidance on safe use of machinery; Categories: Machine Safety, European
       Directive 98/37/EC on machinery (EG), Directive 94/9/EC on equipment and
       protective systems intended for use in potentially explosive atmospheres (ATEX).
      The supplier should assure the equipment is designed in conformity with at least
       the following applicable instructions on work safety:
a.     EN 12100-1; 2004-04; EN 12100-2; 2004-04
b.     EN ISO 13849-1:2006-11
c.     EN 13850:2006-11
d.     EN ISO 13857: 2008-03
e.     EN 349
f.     EN 1088:2007-4

5.3.   Pressure Reducing Valves

      The supplier should include into the offer any pressure reducing valves that are
       considered necessary.

6.     Plans and Documents

2 copies of paper documentation and one CD in Russian and 1 copy of documentation in
English should be attached to the equipment. Documents should be in А4 format.
Drawing of mechanical and electric assemblies may be in А4 to А0 format. Drawings in
electronic form are presented in *.pdf format. Only SI units should be used.

Document package should comprise the following:
    Shipment description,
    Equipment technical characteristics,
    Machinery scope of use,
    Operating manual,
    Process description,
    Electric and electronic scheme,
    List of instrumentation (with detailed information),
    List of inputs/outputs,
    Cable testing documentation,
    Instrument calibration documentation,
    Technical data sheets and instructions for individual assemblies,
    List of spare parts and their catalog numbers,
    List of supplies,
    List and drawings of fast-used assemblies and parts,
    Certificates for metal and non-metal materials contacting with the product, list of
     acceptable lubricants.
ITB No. 15003349                                                                Page
7.     Inspecting visit / Acceptance Testing

An inspecting visit of the supplier’s manufacturing site by the customer’s representatives
and performing on-site pre acceptance testing of equipment may be specified between the

8.     Installation of the Equipment

The supplier installs and mounts the single machineries (equipment) as an interconnected
production line.

9.     Commissioning and Validation at Customer Facility, Training of Personnel

9.1.   Support of quality control

The supplier should assign at least one competent setup engineer (with excellent
command of English language) to the beneficiary’s facility to fix any issues of
acceptance, mounting and setup of the delivered equipment. Following tasks have to be
carried out:

Check the installation of equipment, equipment start-up and commissioning according to
the approved commissioning working schedule, including calibration of important
equipment, scales, etc.

9.2.     Acceptance control at the operating site

The supplier is requested to provide sample documentation on commissioning during
technical/commercial meeting.

9.3.     Training of the personnel

The manufacturer shall provide on-site training for technicians and operators. The
training should include the following:
         The operation theory of all mechanical and electrical systems
         Routine maintenance procedures
         Operation and control of equipment, all sensors, controllers, etc.
         Mechanical switching and installation.
         A training offer of usually required number of training days should be provided
          based on the number of “men-days”.

ITB No. 15003349                                                                  Page
9.4.     The supplier should provide the following validation services

1)       Present the detailed installation qualification (IQ) and operation qualification
         (OQ) protocols for agreement, before carrying out the actual installation.

2)       the supplier should perform the validation requirements, according to the

        Demonstrate conformity to the Specification.
        Present documents demonstrating that software was developed according to
         approved Good Automated Manufacturing Practice (GAMP) protocols,
         especially complying with GAMP-5 prepared by GAMP forum.
        Present project qualification drawings within the period stipulated.
        Register all changes and inform the beneficiary of all changes performed.
        Agree to inspection during manufacture and testing (if necessary)
        Ensure that the product operates according to the specification.
        Present documented verification of testing.
        Present authentic execution drawings.
        Present instructions on actuation, operation and maintenance.
        Present calibration certificates for scales and probes as well as Material
         certificate of conformity (if necessary).
        Present calibration certificates for the entire testing equipment to a pre-specified

The supplier is requested to perform the validation tests at Beneficiary’s facility and
register all data in prepared protocols, authorized by representatives of Beneficiary.

The supplier is responsible for equipment compliance with testing procedure; if any faults
appear, it should perform the necessary modifications and retest the equipment against
the requirements.

9.4.1.   Specification of Installation Qualification (IQ)

Installation qualification (IQ) is a formal documented inspection of the machinery to test
that all installation specifications are met and that the equipment meets specifications.

IQ should include, but not limited to the following:
I)       Description of product and functions.
II)      IQ requirements and scale.
III)     Component registration and qualification, checking that documentation is
IV)      Execution drawings and mounting qualification.
V)       Maintenance and connections qualification.
VI)      Conformity certificate for materials in contact with the product.
ITB No. 15003349                                                                     Page
VII)     Hydraulic testing certificate (if applicable)
VIII)    Certificates of all blast-proof components (if applicable)
IX)      Testing equipment and its calibration date.
X)       Calibration of all important equipment.
XI)      Conclusion, which clearly formulates whether the product has been qualified
         successively or not.

9.4.2.   Specification of Operational Qualification (IQ)

Operational Qualification (OQ) demonstrates according to the formal protocol that
equipment will be operated according to all expected ranges of operating mode.

The OQ protocol should include:
I)      Description of product and functions.
II)     OQ requirements and scale.
III)    References to manual, regulations, etc. that should conform to OQ.
IV)     Test equipment and its calibration date.
V)      Testing aim, methods and acceptance criteria.
VI)     Testing results.
VII)    Conclusion, which clearly formulates whether the product has been qualified
        successively or not.

10.      Documentation standards

1)       All certificates should be dated and signed.
2)       Calibration certificates of the instruments should specify the period of validity.
3)       All technical control sheets should be dated and signed against each item (ticks
         and crosses are not allowed).
4)       Acceptance limits should be stated for each estimated parameter.
5)       Any results differing from estimated parameters should be followed by a
         detailed explanation.
6)       Any changes or amendments in documents should be signed and dated.
         Correcting tools should not be used. Text under correction should be stricken
         through with a single line, signed and dated.
7)       Documents should include a conclusion detailing qualification and position of
         each signee.
8)       Drawings should have notes indicating that drawings have been checked.
9)       Position and affiliation should be stated for each protocol signee.

11.      Delivery and guarantee requirements

        The supplier should give guarantee for a minimum period of 12 months
         including after sales service from the date of delivery to the end user.

ITB No. 15003349                                                                   Page
           Items should be delivered within 6 months from the date of the confirmed order.

           Items should be delivered to Beneficiary. The exact address will be provided
            upon award of contract.


Technical table
       UNIDO REQUIREMENTS                                       TO BE COMPLETED BY THE INVITEE
Item               Name and required parameters              Compliance*) yes/no     Remarks**)

       Equipment, parts, supplies
       Machine functions
       Feeding table
       Product filling and can sealing module
       Transporting and loading device
       Can crimping automatic module
       Propellant filling machine
       Weight checking module
       Crimped valve – aerosol can leak-proof
       checking module
       Coding device
       Product supply recirculation system
       Control system and instruments
       Wearing spare parts

*) compliance must be confirmed in detail in the by the
contractor’s offer and technical documentation and will be
verified by UNIDO during technical evaluation;

**)if not compliant with UNIDO’s required parameters, the
invitee must indicate his parameters in this column

ITB No. 15003349                                                                      Page
UNIDO RFP reference No.
Scope of supply
Commercial table
       UNIDO REQUIREMENTS                               TO BE COMPLETED BY THE INVITEE
Item       Name and required parameters      Quantity    unit price         total item price
                                                         currency              currency

       Equipment, parts, supplies
       Machine functions
       Feeding table
       Product filling and can sealing
       Transporting and loading device
       Can crimping automatic module
       Propellant filling machine
       Weight checking module
       Crimped valve – aerosol can leak-
       proof checking module
       Coding device
       Product supply recirculation system
       Control system and instruments
       Wearing spare parts


       Cost of transportation

       Cost of Insurance (if applicable)

       Total price:

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