Designing architectural drawings of factory facility

We have elaborated architectural design of the factory plant facility.

Technical drawings of a plant

Architectural part

Green field construction finished dosage forms production plant belonging to Ecological Safety Class 5 shall be planned taking into account possible future extension of the building in the Industrial Park . The construction site (marked No. 25 on the General Layout) is triangular shaped with total area of approx 3.9 ha. The following restrictions shall apply to this land plot: when developing the land plot, the production facilities are to be located so that their 50 m wide sanitary-hygienic zone, as per sanitary standard, did not extend beyond the land plot south boundary (this is  strong requirement), the west half of the land plot is located within the boundary of the third belt of the existing well water conservation zone. The land plot surface is mainly flat, with maximum relief height differential of about one meter. The access roads shall be designed to connect to the existing motor road located at the south-west side of the land plot. The utilities connection points are located at 30 meters' distance from the land plot boundaries: the water-supply line - along the north-east boundary of the land plot; the gas line, the rain water sewage line and power cabling - along its north-west boundary; and the domestic sewage line - at the south-east side of the land plot.

General Layout

The future enterprise premises shall include the following facilities and areas:

• Gate House (shall be located at the land plot entrance)
• Main Building (production area, raw material and finished product warehouse, amenity, administrative, laboratory rooms, auxiliary and technical rooms - in the same building) shall be located in the middle of the land plot
• Auxiliary facilities for utilities (boiler house, transformer house, process waste water basin, rain water treatment plant, fire water reservoir and pump station, underground diesel fuel storage tank and waste collection area) shall be located behind the Main Building, along the perimeter of the trucks turning circle, to the right of the existing well water conservation zone
• Car and truck parking lots
• Car, truck, fire engine and pedestrian roads and spaces
• Green spaces
• Premises fencing

Traffic Routes

The enterprise premises access road shall be a turnoff from the future motor road designed at the south-west side of the land plot. Trucks shall enter through the main entrance to the entrance area and truck temporary parking, then to truck turning circle at the warehouse loading/unloading bays, and back to the exit from the plant territory. Cars shall also enter through the main entrance along the road or across the temporary parking to the parking lot at the Main Building portal (main entrance) and back. Fire engines shall enter the site through the main entrance to the entrance area, then along the roads around the Main Building, with free access to the Main Building and all auxiliary facilities for utilities. Traffic shall be one-side till exit from the plant territory as per the existing standards. Pedestrians shall walk along the dedicated roads, sideways, stairs and ramps.

Technical and Economic Features as per General Layout

land plot area 20000 m2 100.00%; build-up area 1000 m2 4.20%; hard surface area 2000 m2 9.36%; greenery area 20000 m2 86.45%.

Architecture

Main Building is a multi-use facility of irregular form. On ground floor in the higher part of the building, the following facilities shall be located: the entrance lobby, amenity rooms, the raw material and finished product warehouse with auxiliary rooms. The laboratory, administrative rooms and warehouse HVAC room shall be located. On ground floor in the lower part of the building, the production area and plant rooms shall be located. Personnel (production and auxiliary) shall enter through the building portal. Access to plant rooms shall be also from the building portal. Trucks shall come to the loading/unloading bays from the back of the building, where the truck turning circle is located. The building structure is of fire resistance rating 2. In accordance with the existing fire standards and regulations, depending on the functional use of the areas, the building shall be separated into two independent fire compartments. In case of emergency, personnel evacuation shall be done along the corridors and the main staircase to the entrance hall and then to the outside, considering not a big number of people working on Floor 1. The auxiliary facilities for utilities with separate entrances shall be located along the perimeter of the truck turning circle.

Structural

The building skeletons are reinforced concrete walls and columns with the proper foundations. Intermediate flooring shall be made of reinforced concrete slabs supported by reinforced concrete or steel beams. Roofs shall be made of panels with mineral-wool insulation and the facing assembled of profiled sheeting and waterproof membrane, installed on the steel beam-and-truss frame. Ground floor slab - cast in-situ reinforced concrete. Fapade walls - precast steel sandwich panels with mineral-wool or other non-combustible heat insulation. The areas with higher natural lighting limits shall have large structures made of transparent glass (laboratories, administrative and production rooms). Depending on functional profile and required fire resisting properties, the internal partitions shall be made of precast panels for clean rooms, certain thickness brickwork or gypsum board sheeting on steel frame.

Fit-out

Technical and Economic Features of Main Building

For floor, wall and ceiling final finishing, good-quality durable materials shall be used, depending on the purpose of certain premises and in accordance with the existing standards. total area        900 m2; usable floor area 100 m2; architectural volume 5000 m3; number of floors 1 and 2 floors.

Technological part. General Introduction

A pharmaceutical company with a strong reputation in gynecology over the last 30 years and is a renowned actor in hormonal therapies for women and men. has its own manufacturing facilities, specializing in the production of products in the fields of gynecology, fertility 8 obstetrics, men's health and nutrition. planning to build a new Oral Solid Dosage (OSD) pharmaceutical production plant in Russian Federation.The Plant will be green-field and stand-alone plant with all support functions required as necessary. The pharmaceutical plant and all manufacturing processes shall comply with the applicable Russian Federation regulatory documents, as well as international requirements of the European Union (EMEA) GMP.

Purpose of Document

The purpose of this document is to define at this stage of project is Master Plan of Plant layout and process rooms layout. The document also serves as the narrative support to the preliminary budget estimate and basis for the Plant layouts. This document will form the basis of all Engineering services on which will be develop the design. The design was undertaken according to a portfolio of OSD products. General project description In new Plant will be produced finished hormonal products in form of soft gelatin capsules. This Plant is separate, dedicated Plant and should not form part of any other non-hormone plants. The new plant shall feature the following key functions:

Production

• Materials receiving . Storage
• Weighing and sampling

Gelatine melting and medicine suspension preparing

Encapsulation. Drying

• Inspection.
• Sorting. 
• Packaging in blisters.
• Packing into cartons
• Packaging into transportation boxes
• Palletizing.
• Warehouse

There is no special requirements regarding storage conditions, except to keep conditions of RH= max 65% and temperature to be 15 - 25 °C. Low bay warehouse; Nominally 2 batches storage of Final products, Raw materials and Packing materials; 270 total pallet storage. Quality control. Physical-Chemical Lab . Microbiological Lab . Sample Archive. Production supporting functions: Administration Offices, Dining room . Waste Collection . Utilities Generation . Site guard and access control Process and Technology.

Technological assumptions

Technological assumptions are directly based on production forecasts, products lists, process descriptions, main equipment list and site preliminary layouts defined and delivered by “Besins Healthcare' in Technical Assigment. Process Basis. Production of final dosage forms from imported API progesterone (prepared hormone). Final dosage forms in OSD-Soft gel capsules, 5 million packs/year (75 % in 200):

• 100: 2 blisters of 14 capsules per carton;
• 200: 2 blisters of 7 capsules per carton.
• Products will be packed in blisters and cartons as a secondary package. Production will be performed in campaign system, organized in 3 shifts, 5 days week (250 working days / year)

Production Program. Solid Dosage Forms Department - Soft gelatin capsules production. Batch definition. Batch is defined as final melted gelatin solution and medicine suspension made in preparation processes and used for encapsulation. Weighing process, as well as, solution preparation, will be performed separately for each sub batch. Batch size: Batch content and size is 2090 kg for continuously encapsulation process is in Table below:

Operational philosophy

The Plant will initially produce nominally on a three shifts, basis (7 hours / day; 5 days / week).The Facility will produce nominally 2 batches per week. During encapsulation operation the production will be organized in three working shifts. Plant and During one production week will be processed two (2) batches. Equipment and facilities generally cleaning will be undertaken after each two batches production as required. Production capacity estimates for key continuous encapsulation and packaging line / equipment is based on: Encapsulation 24 hours / day actual operating time (three shift); Sorting and loading 16 hours / day actual operating time (double shift); 5 days I week; 40 weeks / year. Cleaning, Retooling etc. can be undertaken on a separate shift as required. Support functions including Warehouse and Weighing, will generally operate on a single day shift

Transfer of incoming goods. All required raw materials (small, medium and large quantities) required for one production batch will be transferred from the central warehouse on request of production personnel. Raw materials will be delivered in original packs via material airlock (MAL) and will be transferred directly to Weighing Room.

Weighing

All raw materials (small, medium and large quantities) required for one production batch will be dispensed in stainless steel IBC bins and drums as well as in plastic bags. All quantities of excipients will be weighed manually on a bench scale or floor scale. Scales will be located in downflow booths under laminar flow to avoid dust propagation and cross contamination during weighing operation. Weighed materials will be added to IBC bins or transferred to process rooms separately (in drums, bags). For API materials will be used Glove box for hazardous material containment. The room and equipment will be used and for raw material and auxiliary material sampling purpose. Preparation of gelatin solution and medicine suspension Gelatin melting vessel and Medicine service vessels will be sized on the basis of being able to handle: 8-hours operation.

This gives volume of 600 liters of Gelatin melting vessel and two service tanks for melted gelatin transfer to encapsulation machine during encapsulation process of 2001 each. Medicine suspension will be prepared directly in one of two service tanks volume of 2001. Encapsulation manufacturing process. After melted gelatin solution transferred to the service vessels, the gelatin and medicine mobile service vessels are then taken to the encapsulation room. Where each of it is connected to encapsulation dosing system of encapsulation machine. The molten gel is pumped to the machine (by compressed air) and two thin ribbons of gel are formed, one either side of the machine. These ribbons then pass over a series of rollers and over a set of dies that determine the size and shape of the capsules. The medicine suspension is fed from its service vessel to a positive displacement pump, which accurately doses the fill and injects it between the two gelatin ribbons prior to them sealing together through the application of heat and pressure.

Capsule Drying process

The first step of capsules drying is performed in Encapsulation Tumble Drying:- by dry, sterile air. After the tumbler dryers, the soft capsules are placed on special trays for final drying in the drying room. For a period up to 48 hrs. Drying room has capacity for two days production. Dried capsules will be collected to stainless steel drums then hermetically closed, labelled and transferred to the intermediate storage or directly to Inspection Room.

Inspection/sorting

nspection/sorting is required for quality checks of all capsules. For these products semi-automatic visual inspection system will be used. Primary packaging. Inspected/sorted capsules will be packed in blisters. Required amount of primary packaging material will be delivered via MAL. Product will be charged from drums, to the feeder of packaging line. Products will be packed in PVC/Alu blisters

Secondary packaging

Welded blisters will be transferred by a conveyor to the secondary packaging room. In this room blisters with added leaflet will be packed in carton unit boxes. On each unit box the batch number and expire date will be coded. After packaging in unit boxes mass of boxes will be checked in-line on check weighing device. Set of unit boxes will be manually packed into transportation boxes.Transportation carton boxes (sell boxes), sealed and labelled, will be collected on the pallet and than transferred to warehouse. These activities will be performed manually.

Cleaning

Main washing area is manually washing room for format parts and equipment. Sink and washing place with floor drain will be installed in this room. Gelatin melting tank will be washed by WIP installed system. After the end of batch production all dismountable elements and auxiliary devices used during production will be transferred to washing area. For preliminary and regular washing cycle will be used the potable water with appropriate cleaning agents. Final rinsing will be done with with Purified Water.

Materials receiving

All raw and packaging materials will be delivered to receiving /shipping area. Trucks will be unloaded with forklifts. Next materials will be checked for conformity with documentation. Each material will be transferred to required area with status "under quarantine” until release by QC. Sampling. All raw materials will be checked by QC department. Samples will be taken in class "ISO 8" Weighing&samplingsampling room under weighing booth. Identification tests will be performed for all batches of raw materials. Tests will be performed in Quality Control laboratory.

Quality Control (QC)

Basis. Functional areas. Quality Control laboratory will be located on level 2 and divided for 2 sub-laboratories:

• Physical-Chemical Laboratory;
• Microbiological Laboratory.

Also on level 2 will be located storage area of raw materials/products samples (reference samples) as well as samples archive. Quality control tests of soft gelatin capsules. Shape and size. Color. Thickness of capsule shell. Leaking test for semi-solid and liquid ingredients from soft capsules. Disintegration tests . Weight variation test. Percentage of medicament test Dissolution test. Personnel. Table presented below show the approximate estimated number of required personnel in whole Plant. The numbers are estimated as basic assumption. Total number of required personnel:

Flows

Personnel Flow. All personnel enter the Site through the main entrance. Next, personnel split in three main groups:

• production personnel
• QA and administration personnel
• Warehouse personnel
• Material Flow

All starting materials required for pharmaceutical manufacturing will be delivered to the Warehouse, where they will be sampled and stored. After release by Quality Control, and according to production orders, materials will be transported to the required production area via the material airlocks (separate for class ’ISO 8" and "CNC" area).

Uniforms washing

All uniforms used in new Plant will be washed out of the Plant (outsourcing) or disposable uniforms will be used. Dining room. There will be Dining room located on level 1. Meals will be not prepared in The Plant. Personel is obliged to change the production/ laboratory uniforms to the private one before coming to canteen.  Cleanness Black. In Black area will be located:

• Administration and offices
• Meeting Room
• Dinning room and social rooms
• Server. All technical areas

Transfer corridors between these areas. CNC. CNC zone will be applied for following areas . Secondary Packaging, QC laboratories (except Claass ISO 8 in MBL). Warehouse. Clean Class "ISO 8”. Clean Class ‘ISO 8" will be applied for following areas: Solid Dosage Forms production from weighing up to primary packaging step. Personnel airlocks for Production area. Seeding room in microbiological laboratory. Product protection. The requirement for producing quality products, are covered by adequate cleanroom classes and number of air changes, regarding process operations, correct temperature and relative humidity in the process rooms, pressure cascade in process airlocks, corridors and process rooms, with respect to contamination and cross- contamination protection of product.

Containment Strategy

The containment strategy describes all measures to control:

• Risk of contamination of product;
• Risk of contamination of environment;
• Operator and environment safety
• Contamination Control
• Separate Premises

In order to comply with basic principals of contamination control outlined in GMP, the following premises (process nests) have been separated with airlocks:

• Weighing,
• Encapsulation,
• Primary packing.

Each separated production area have independent:

• Production Equipment
• Airlocks

Air supplied with HVAC System (no recirculation between nests). Exhaust air from those rooms will be locally filtered through "Bag in bag out" HEPA filters.

Pressure Cascade

The sense of applying a pressure cascades is:

• Ensuring required cleanness in production premises;
• Minimizing of contamination risks;

Following basic principals are applied:

Between class ISO 8 and adjacent CNC area is pressure difference of min. 7,5 Pa, increasing to the cleaner side. In order to reduce the risk of contamination within the ISO 8 production area, an airlocks with pressure difference between production corridor and production rooms are applied (the number of airlocks and pressure cascade depends on risk level identified inside the specific production room). Airlocks between ISO 8-dass, CNC and Facility Black zones are forming a pressure cascade against outside areas. Operator and environment safety. For production purposes API and excipients materials are applied. Generally, these materials may be categorized in following main groups: Active substances (API). Part of a drug causing the desired reaction in a human body. NO gene-manipulated, bacterial or virus-based, narcotic or cytostatic substances are used. All active substances are categorized in OHC hazardous groups (OHC - Occupational Hazard Category) from 1 (low potent, 10 mg/m3-1 mg/m’) to 6 (high potent, below 0.01 pg/m1). These substances are - in higher concentrations then stated in the OHC - hazardous; pollution of these substances to outside have to be strictly minimized or eliminated.

Excipients

Part of a drug enabling a human body to absorb the active substances, controlling the time of absorption, and giving the drug an acceptable form, taste and color. Mainly well-digestible organic substances, such as sugar, lactose, potato starch, vitamins. These substances are non-hazardous; however, the pollution to outside should be also minimized while employing appropriate procedures or technical methods. Packaging Materials for primary and secondary packing Materials are: Plastic Foil (PE, PVC, PU), Aluminum Foil, Paper (printed Leaflets), Carton (partially printed, - coated). Pollution of these Materials is not possible; However, remaining materials must be disposed as solid waste. The processes carried out within the plant may be categorized in the following Groups:

• High requirements
• Enhanced requirements

Standard Requirements

High requirements. Critical processes are in generally the processes with: OPEN handling of ACTIVE substances which are DUSTY. In new plant the most critical process is weighing of active substances class “OHC 4, -5 and -6": Scale of operation is medium (kilograms) duration of the task (weighing) is short (< 30 min) dust potential is "medium" (Granular or crystalline, visible dust, settles quickly), EP (Exposure Potential) is category 2 (from EP 1 to EP 4,1 = lowest, 4 = highest). The Operator must be protected against contact with these substances in an appropriate manner. In the new plant, the following systems are foreseen in order to provide this protection: Isolator with direct connections for weighing of API class "OHC -3, 4, -5 and -6", Downflow weighing booth with air barrier for weighing of API class "OHC -1 and -2" providing operator's protection by a laminar downflow air stream.

Processes

Enhanced requirements

Enhanced requirements are applicable in ALL other processes with handling of substances, carried out in direct production rooms of clean class "ISO 8", which means: Weighing (Excipients and active substances class "OHC -1 and -2"). Solution Preparation; Primary Packaging; Washing; In such areas, operators shall wear appropriate protective clothes, such as gloves and textile masks. Handling of substances shall be as much as possible hermetized, open handling is limited to some short activities.

Standard Requirements

Just standard requirements are applicable in ALL production processes carried out without involvement of substances, or with already closed products, which means for example:

• Warehousing
• Secondary Packaging
• Internal Transport
• Administration

Technical Support / Maintenance. Process Equipment.All process machines are single units, with integrated automation systems.They will be purchased as package units, including related Validation protocols.A list of currently foreseen Process Equipment is of course preliminary, and subject to possible modifications during the next project stages

Clean services

The following will be provided to support soft gelatin capsules manufacturing:

• Purified water
• Vacuum
• Compressed air
• COP (Cleaning Out of Place)
• WIP (Washing in place)

Local exhausts. Clinical trials / Product development facilities will not be included

Utilities. The Energy area will be located in a separate building as per Russian norms. The following utilities / services will be provided. Hot water:

• Potable hot/cold water;
• Firewater;
• Compressed air;

Wastewater collection facility: Solids waste storage. There is no provision for an onsite incinerator. All waste (contaminated and non- contaminated) will be removed for offsite treatment/disposal. A backup generator will be provided. This will only be sized to support a small number of defined essential loads - which are yet to be established.

Wastes

Oust and gaseous waste During production process, atmospheric air intake and exhaust will occur in order to maintain proper parameters of production environment. During manufacturing process, solid wastes (dust) will be generated. The generated dust represents an average mixture of all dusty substances and products handled in the Plant. Gaseous wastes (vapors) will NOT be generated. Ventilation systems of pollutants emitters are directly connected to air exhaust system. In order to limit emissions, exhaust system will be protected with anti-dust filters, preventing dusts emission into the atmosphere.

Solid wastes

Methods of solid wastes treatment:

• All waste will be properly packed and labeled with information on type and appropriation of waste material, segregated and collected in proper baskets or containers in place of their generation.
• Packed wastes will be handed over to company authorized to industrial waste disposal (including overdue drugs).

It will be treated in a special way depending on waste material type. Wastes that are not contaminated shall be subject to disposal by any authorized company

Liquid wastes

The process sewage system will be used to drain water from the technological processes. Process sewage generated during plant operation will be only in the form of washing water, as a mixture of cleaning water (City Water or Purified Water) with rests of solid materials remaining on equipment to be washed. The rests of these materials represents an average mixture of substances and products handled in the Plant. It is assumed, that the waste water of all production and laboratory units should be discharged together directly to the local storage tank. Whole amount of process sewage will be pumped to the waste removal trucks and handed over to the companies authorized to their utilization for further pre-treatment and neutralisation activities

Monitoring of emissions

Emissions to Air

Due to intended production type and risk of emission of detrimental matters into the atmosphere it is planned to provide monitoring of such pollutants. The main agents emitted into the atmosphere will be impurities contained in the air supplying facility in the scope of air-conditioning and ventilation. The main pollutant will be dust of solid materials applied for production, which - despite use of emission reduction system - may be emitted into the atmosphere. The amounts will be minor; however, due to the risk of their occurrence emission volume shall be controlled. Monitoring shall be carried out by:

• Monitoring of all applied Filters (pressure-drop, grade of impurity) of air-conditioning and ventilation-systems within the plant.
• Test Analysis: drawing samples in sampling points (air outlets) and performing qualitative and quantitative analysis by the chemical-analytical laboratory.
• GMP/HSE (health safety and environment) requirements

Introduction

Products are manufactured for sale in the Russian Federation. Segregation. There is no need for segregation because of production of only one preparation. Batch record / Validation: Paperless validation is not required. In principle manual records supported by bar codes will be utilized. Flammable materials / Electrical area classification / Explosion protection. No flammable materials will be present other than small quantities (<5 litre containers of disinfectants) whose use will be strictly controlled through procedures. ATEX classified equipment and electrical apparatus is not foreseen. Environmental protection. To be determined during Stage P execution. No hazardous emissions are foreseen. All waste (both contaminated and non-contaminated) will be removed for offsite treatment/disposal 14. Utilities -Summary

Purpose of Document

The purpose of this document is to approximate the demand for energy sources for obtaining Eechnical Conditions from the Local Authorities and for communication with the Service Providers. At this stage of project development the figures enclosed can only be considered indicative and have been extrapolated from similar type facilities in Russia. The actual requirements will be established during Stage P development.

Utility loads

Preliminary site battery limit figures:

It is assumed, that the waste water of all production and laboratory units should be discharged together directly to the local storage tank. Whole amount of process sewage will be pumped to the waste removal trucks and handed over to the companies authorized to their utilization for further pre-treatment and neutralisation activities.ln the future.will be built processing system stchnyh process water. And then, purified of effluents will prisaedineny bit to drain.

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