URS (User Requirement Specification) Sterile API Facility

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 USER REQUIREMENT SPECIFICATION

                   STERILE API FACILITY

1.0 Introduction

 1.1 Scope of the Project:

                                                         

The project envisages setting up of a Greenfield Sterile API manufacturing facility and new Quality control / Quality assurance / Micro Biology Block within the current property boundaries of Aurobindo Pharma Ltd., Unit-V at Pashamylaram in Hyderabad. The entire project shall be designed in such a manner that it complies with the cGMP requirements/guidelines of US Food & Drug Administration (FDA), UK Medicines Control Agency (MCA), World Health Organization (WHO), European union and other relevant regulations and standards both national and international.

The project includes:

  • Construction of green-field Sterile API Production Block
  • Construction of QC Laboratory, Q.A., Microbiology labs.
  • Installation, testing and commissioning of HVAC (Heating, Ventilation & Air conditioning).
  • Installation, testing and commissioning of Electrical Systems.
  • Installation, testing and commissioning of Process Equipment.
  • Installation, testing and commissioning of Process Piping and Utilities Piping.

1.2 Scope of the Document:

 

This document gives user requirements specifications for Sterile API manufacturing Facility, to facilitate design and implementation of the project.

2.0 Project Basis

The entire project shall be designed, which shall comply with the cGMP requirements/guidelines of US Food & Drug Administration (FDA), UK Medicinal health and regulatory authority  (MHRA), World Health Organization (WHO) and other relevant regulations and standards both national and international. The facility shall be designed to accommodate three production modules independent of each other including final powder processing. For raw material storage and finished goods storage a common area to be identified considering the manpower requirement and ease of operations like dispensing, sampling and transfers.

3.0  Project Site Location and Environmental Conditions

The site for the construction of the new manufacturing facility is located within the industrial estate, at Pashamylaram, which is approximately 35 km from Hyderabad in India.

The site has sufficient area for the development of facility.  The facility shall generally be self-supporting but shall use some existing site services.  The proposed site is clear of any obstructions or underground services.   The soil condition is good and suitable for normal foundations without the need to go for pile foundation.  The site does not come under earthquake prone area.  However, all the structures shall be designed assuming that the site falls under Zone-2 category from the point of view of earthquake prone area.  The weather conditions are same as that prevalent in Hyderabad city.

Segregation of vehicle access and movement, and personnel access and movement is achieved both at the site entrance gate and along the internal roads and designated pedestrian footpaths.

The Production buildings are located centrally within the site.  The Central Engineering, Utilities and Waste Disposal areas are located at a remote low corner away from the site entrance and the rest of the buildings.

The facility shall be designed to accommodate two production streams independent of each other, with a flexible layout, which shall permit upgrading/minor expansions, packing & storage area.

3.1 Facilities

The site will be developed to produce a range of Semi synthetic Penicillin products, the project initially will be divided into two phases, phase I and phase II.

3.1 Sterile API Production Building

This will include the areas listed below, together with their necessary support areas:-

  • Raw material hold area
  • Primary packing material receipt and dedusting area.
  • Finished goods and Secondary packing material Ware house.
  • Charcolisation area
  • Solution preparation area
  • Sterile filtration area
  • Sterile crystallization, centrifuge drying and Filling area
  • Blending area
  • Washing and Sterilization area.
  • Sealing and Quarantine area.
  • Secondary packing area.
  • Change rooms and other support areas.

3.3 Building Design Philosophy

The Sterile API manufacturing facility is intended to have production buildings to manufacture Semi Synthetic Penicillins.

The production building shall be developed with the flexibility to allow for additional accommodation to be easily incorporated in the future to respond changes in capacity requirements, materials stock hold and shift patterns.

The building design shall incorporate accommodation for future expansion also where space shall be provided for the equipments which shalll not be installed until a future date. In this way, the ability to quickly and easily respond to production increase demands can be incorporated without the risks of compromising the operation.

When production volumes continue to grow, then the modular design shall be considered for stage-wise expansion of the relevant areas of the facility, without causing undue disruption to the then ongoing operations.

The corridors and manufacturing areas shall be provided with glazed wall panels to enable good visibility to the operators within the manufacturing rooms, and also enable visitors to view the operations from corridors without the need to access the manufacturing environments.

The production building shall be designed as a controlled area, within which there will be two categories:-

  • Areas where product is not exposed (i.e. Secondary packaging.)
  • Areas where product is exposed to the processing environment i.e; manufacturing areas.

All these areas shall be provided with appropriate finishes and air quality to comply with the cGMP guidelines relevant to their stage of the process.  In the areas where the product is exposed during operations, the environment (both air quality and finishes), shall be of the highest standard appropriate to the product and process stage.  Instead, where the product is in its final packaging (e.g.: Finished goods packing area and Finished goods stores), provision is required simply to ensure that storage conditions are sufficient to prevent degradation of the product, which will reduce its shelf life.

In terms of environmental finishes and air quality, each change area and airlock, shall be designed & maintained to the level of the higher standard area.

3.4 Internal Finishes

Appropriate standards of internal finishes shall be provided in each area of the production building to meet the relevant GMP Guidelines.

Grade ‘A’ areas

Grade A defines a Cleanliness class of ISO 5 i.e; Laminar Air Flow (LAF) environment.  Typically this is the environmental requirement at the point of fill for a sterile product.   This will be achieved by specifying the use of LAF over the sterile products filling and Sealing lines, Autoclave and DHS loading and unloading areas.

The Air handling units and Building Automation systems shall be designed with a provision for Fumigation cycle.

Grade ‘B’ and ‘C’ areas

Grade B defines a Cleanliness Class ISO 6 environment.  This is for the sterile product filling room environment, cooling zone and Buffer blending area and Quarantine area.

Grade C defines a Cleanliness Class ISO 7 environment.  This is for the sterile change room-2 area.

Classification and achievement of Grade B and C areas is measured in the un-manned (at rest) condition.

These conditions shall be achieved by the use of terminal HEPA filters in the air supply to the room, which should exhibit high level supply and low level extract of air, a minimum of 60 air changes per hour, and a minimum of 15 Pascal pressure differentials from an area of lower classification and 5 Pascal’s between rooms in the same classification.  Grade B and C areas should be protected by airlock and separate personnel change for entry and for exit.

The Air handling units and Building Automation systems will be designed with a provision for Fumigation cycle.

Walls – specialist factory produced modular SS or GI powder coated wall panels.

Ceilings – Coved at the junction with the walls; specialist modular ‘walk on’ type ceiling panels.

Floors and covings- Epoxy resin with integral coving on prepared substrate; coved at wall junctions.

Doors – Specialist produced integral stainless steel doors with double glazed vision panels and frame sets.

Internal glazed panels – Metal framed and powder coated or Stainless steel framed, double glazed flush with wall surfaces and silicone bead all around.

Grade ‘D’ areas

Grade D defines a Cleanliness Class of ISO 8 environment at rest and is recommended for non-sterile processing operations e.g.: Charcolisation, Solution preparation area, GMP corridors, Solvent filtration areas, washing and sterilisation area etc.

These conditions shall be achieved by the use of a Terminal HEPA filter nearer to the room, a minimum of 25 air changes per hour, and a minimum of 15 Pascal pressure differentials from an area of lower classification.  Grade D areas are protected by airlock and personnel change common for entry and exit.

Walls – Brickwork rendered both sides and epoxy on prepared wall substrate; coved at junctions and corners / Specialist factory produced modular GI Powder coated wall panels.

Ceilings – Coved at wall junctions, Painted with epoxy / PU paint on prepared ceiling substrate to underside of concrete slab above;

Floors and coving- Epoxy resin with integral coving on prepared substrate;

Doors Specialist produced integral metal doors with double glazed vision panels and frame sets.

Internal glazed panels Aluminium framed double glazed flush or near flush with wall surfaces and silicone bead all around.

Socially clean areas

Socially clean area defines a 5 Micron filtered air environment is recommended for Circulation corridors, Secondary packing areas, finished goods Quarantine and storage areas etc.

Walls – Suitable quality Emulsion paint on prepared, cement rendered masonry walls; no coving at junctions and corners.

Ceilings – Suitable quality emulsion paint on prepared substrate; or Gypsum board false ceiling system.

Floors and coving– Epoxy paint on prepared screed substrate with non-coved skirting.

Doors Specialist produced integral metal doors with double glazed vision panels and frame sets.

Internal glazed panels – Aluminium framed single glazed with sloped sills shall be considered.

3.5 Internal Design Conditions

The internal environmental conditions provided by the various HVAC systems particularly in the GMP areas shall be subjected to appropriate levels of monitoring and qualification to confirm that they remain within the predefined compliant operational range continuously 24 hours/day, 7 days/week.

Appropriate levels of lighting shall be considered throughout the facility in accordance with local regulations; however the lighting levels stated below shall be considered as minimum requirement in the specific areas listed:

  • Manufacturing areas                                       500 lux at working plane
  • Laboratories and Write Up areas                    500 lux at working plane
  • Non GMP Manufacturing , Packing areas        300 lux at floor level

            Summary of Internal design conditions:

Sl.no Area Cleanliness class No. of air changes Temp.  °C RH in % Finishes Lighting levels ( in lumens)
            Ceiling Walls Flooring  
1. Sterile filling & Sealing area ISO 5 Not specified 22±2 Nmt 30 Specialist modular walk on type ceiling panels.

Coved at junction with walls.

Specialist factory produced modular SS or GI powder coated wall panels.

Coved at junctions and corners.

Epoxy resin with integral coving on a prepared substrate. 500
2. Surrounding environment of sterile filling area , Cooling zone, Quarantine ISO 6 Minimum 60 22±2 Nmt 30 Specialist modular walk on type ceiling panels.

Coved at junction with walls.

Specialist factory produced modular SS or GI powder coated wall panels.

Coved at junctions and corners.

Epoxy resin with integral coving on a prepared substrate. 500
3. Washing and sterilization areas, Sterile filters area, Solution prep. Area, Charcolisation area. ISO 8 Minimum 25 28±2 Not specified. RCC slab painted with Epoxy, coved at wall joints. Brick walls rendered on both sides and Polyurethane paint on prepared wall substrate. Epoxy resin with integral coving on a prepared substrate. 400
4 Office, IPQC, Secondary packing area and Ware house Socially Clean Minimum 10 28±2 Not specified. RCC slab painted with suitable quality Emulsion paint, coved at wall joints or Gypsum board false ceiling system. Brick walls rendered on both sides and suitable quality emulsion paint on prepared wall substrate. Epoxy resin with integral coving on a prepared substrate. 300

 3.6 Process, Process support and Utility systems:

The GMP requirements for Process, Process support and Utility systems shall be based on the concepts of product exposure, level of protection, and critical parameters and systems.

  • Process systems in this context refers to the systems which are:
  • In contact with the drug substance in its purified or unpurified state
  • In contact with materials which ultimately will become, or be in contact with, drug substance.
  • In contact with a surface which will contact product.

The piping for clean utilities shall be designed in such a way that the dead legs are as per the acceptance criteria prescribed by US FDA regulatory authorities and the piping shall have adequate slope to ensure drainability.  The water for injection and purified water shall be designed to have continuous loop system.  The other services such as electrical, chilled water, plant steam, inert gases(for blanketing), vacuum, Nitrogen (in both liquid and gaseous forms), compressed air etc., shall be designed to meet the process requirements. Utility matrix is enclosed as Annexure 8.

3.7 Manpower and Working Pattern:

The facility is envisaged to be operational on a continuous production basis.  This is based on a 24 hour, three shift system.  The personnel’s working per shift are as under:

                                                                  Module-1                     Module-

Shift-1

                  Process

                  Engineering

                  Others

Shift-2

                  Process

                  Engineering

                  Others

Shift-3

                  Process

                  Engineering

                  Others

            General Shift

                        Process

                        Engineering

                        Others

The change facilities shall be designed to service the personnel as estimated above with an additional allowance for visitors.

3.8 Access and Garment Regime

All personnel entering the production buildings shall leave through an appropriate garment changing regime.

The garment change regime shall be designed to give, both product and operator an appropriate protection against contamination.  Therefore, variations in garment shall be required in production areas where there are differing product risks (e.g.: sterile areas).

Where the “outward” garment change is separated from the “inward” garment change, provision shall be made for the exiting personnel to retrieve the garments they shed when they enter that area.

All personnel shall be provided with a personal locker where they can securely leave the outer clothing and shoes as they arrive at work, together with any other personal items.

After Hand and Foot wash, all personnel are expected to change into a general factory uniform collected from dedicated lockers and put on their “factory shoes” kept in the change room.  This general factory uniform will provide personnel with access to the general circulation corridors, secondary packaging areas, etc.

The garments shall be delivered clean from the laundry to the designated lockers within the appropriate changing room and be discarded into appropriate containers at the end of the shift, for collection by the relevant laundry personnel.

Access to the aseptic manufacturing areas shall require a complete change of garments of the working personnel into a dedicated sterile area garments.

Visitors shall be expected right from their arrival at the building to use the change facilities provided exclusively for them and have access to GMP corridors. However if they intended to enter the manufacturing Module then they shall follow the same change procedure as the production personnel of those areas, and change into the same standard of garment designated for that area.

Eating and drinking provision shall not be given within the production buildings.

3.9 Other requirements:

The facility shall be provided with fire alarm and control systems, emergency lighting, etc. in addition to general safety norms such as emergency exits and Central management System with required Hardware and Software to control and monitor the Field Control System.

The following equipment and accessories, wherever applicable, shall be covered  under the Integrated Building Management System.

Equipment Control Monitoring
Chillers
Primary Chilled water Pumps
Secondary chilled water pumps
Condenser water circulation pumps
Cooling Towers
AHUs
Ventilation Supply air fans
Ventilation Exhaust air fans
Door interlocks
Temperature , RH and Differential pressures
Fumigation cycle
Fire alarm systems

The laundry shall be provided with Class 100000 clean zone and Pressing and Packing of the garments shall be carried out under Laminar flow unit.

3.10 CIP / SIP CONCEPT

Cleaning and Sterilizing in place (CIP / SIP) provision for the equipments shall be considered with due importance during basic designing of the layout.

  • Documentation:

A well planned road map defined, as validation master plan shall be prepared to compile the documents required for the facility.  The documents shall include design reviews, layout drawings for execution, as built drawings, etc.  A list of documents required to be prepared shall be made to ensure that all required documents are prepared and kept as documented evidence for all activities.  A comprehensive documentation package consisting of the following documents shall be prepared:

  • User requirement specifications
  • Validation Master Plan (VMP)
  • Design Qualification (DQ)
  • Installation Qualification (IQ)
  • Operational Qualification (OQ)
  • Performance Qualification (PQ)
  • Process Validation (PV).

3.12 Water Analysis Report

Water analysis report for the preparation of purified water generation and Water for injection system specification is as per the Annexure-6

4.0 Operations

4.1 Proposed products manufactured in the Facility

The following products are proposed in the Sterile API manufacturing facility on a campaign basis.

  • Amoxycillin sodium
  • Azlocillin
  • Mezlocillin
  • Nafcillin
  • Piperacillin
  • Ticarcillin
  • Sulbactam sodium
  • Tazobactum
  • Oxacillin sodium
  • Dicloxacillin sodium
  • Flucloxacillin sodium
  • Sultamicillin tosylate

A general Process Block diagram of sterile manufacturing facility shall be as per Annexure No.9.

4.2 Sterile Semi synthetic Penicillin’s manufacturing Process.

The raw material will be obtained from APL Non sterile bulk facility nearby; therefore it has been assumed that no further processing is required.

In general the Non sterile product shall be dissolved in 3-4 times of water. The solution will be treated with Carbon, filtered and transferred to another reactor in Non sterile area solution preparation room. It will then be filtered through series of filter and transferred to sterile reactor. Sodium salt will then be allowed to Crystalline by adding the anti solvents like acetone, ethyl acetate or alcohol. These solvents will be filtered through a micron filter before charging. The slurry will then be centrifuged or filtered. Washed with solvent and dried.

The dried product shall be transferred by means of Pneumatic conveyor to Co mill, where it shall be sized and sieved and is transferred under closed conditions to a filling machine for filling and then transferred for weighing.

Adding of the Buffer shall be carried out in the Blending room, which will be isolated from the Filling area. Filling and Sealing be provided separately of the Blended material.

It is assumed that this operation shall be carried out on a campaign basis.

4.3 Production Capacity:

The facility shall be designed for a capacity of 4.4 Tonnes / month and the batch sizes shall be around 100 kgs. The finished shall be packed in Aluminum canisters of 20 lts or 25 lts. The capacities of the equipment shall be planned according to these volumes.

List of major equipment proposed to be installed in production Module-1 is furnished below:

Sl No. Description Capacity MOC Qty
Slurry preparation tank   SS 316 L 1
Carbon treatment reactor   SS 316 L 1
Plate and frame filter   SS 316 L 1
Solution preparation tank   SS 316 L 2
Filtration Train 5 µ, 1.2 µ, 0.22 µ   3
Crystalliser   SS 316 L 2
Centrifuge Dryer 35 kg dry powder SS 316 L 1
Filter separator   SS 316 L 1
Co-Mill   SS 316 L 1
Auto Canister filling machine   SS 316 L 1
V – Blender   SS 316 L 1

In addition to the above equipment, the facility shall also be provided with other equipment for media/buffer preparation, wash, fill & finish processes.

4.4 Capacity Calculations

The equipment needs and capacity calculations are based on the following assumptions:

  • 312 working days per annum, based on 52 weeks and 6 days per week
  • 8 hours per shift
  • Three shift working

4.5 Storage Requirements

The Raw materials and Primary Packaging materials (Aluminum canisters) shall be stored in Non Sterile production block and shall be transferred based on the production needs to the sterile manufacturing block.

In addition space has been provided for the Secondary Packaging materials & Finished goods.

The warehouse dimensions have been based on estimated pallet quantities required to hold the stock levels of 15 days.

4.6 Transfer of Samples to Laboratories

Various items need to be transferred from the production buildings to the Laboratory buildings:

  • Samples from production processes
  • Samples from packaging lines and finished packed products

Routes shall be considered within production building to enable samples and items to be transferred to the Labs in such a way as to avoid personnel having to pass from one environmental classification to another.

4.7 Laboratory Requirements

The laboratory requirements will be provided which will need to accommodate:

  • Quality Control Analytical Testing Laboratories;
  • Quality Control Microbiology Laboratory ;
  • Support functions.

The lab will be designed to meet international standards with reference to Good Laboratory practices. The lab will be equipped with state of the art equipments and analytical instruments like HPLC’s, GC’s, FTIR, UV Spectrometers, Dissolution apparatus, Autoclaves, Ovens, and Incubators. The lab facility shall be designed to have Wet Chemical lab, Instrument lab, Microbiology lab, Stability rooms, Control samples room etc. The Environmental conditions of the Micro lab will be similar to the manufacturing area.

Separate Documentation storage room will be provided where all the documents related to the facility will be stored. The access shall be only for authorized personnel only.

4.8 Validation

This facility will comply with the EU and FDA GMP regulations, be able to successfully sustain GMP regulatory inspections and be able to export its products to the markets regulated by these authorities.  Therefore the facility, its utilities and equipment will need to be qualified, and the processes validated.

Successful qualification will demonstrate that the facilities, utilities and equipment are fit for purpose and can repeatable perform to the required parameters.  To ensure a successful qualification to EU and FDA requirements, the necessary tasks shall be planned from an early stage of the project and to integrate them with the design and construction programme.

Appropriate requirements for this have to be written and included in the detail design and technical specifications of the facility, utilities and equipment packages, so that the necessary documentation needs are defined and incorporated into their purchase orders.

4.9 Production Start-up

The facility start-up shall be planned as a project in its own right that will run in parallel to the design, construction, installation and qualification of the facility.

Start-up planning will need to encompass:

  • Preparation of a recruitment and training plan
  • Writing of production, engineering and QA/QC SOPs
  • Set-up of site documentation e.g. Site Master File, Batch Manufacturing documents, QC Testing documents, etc
  • Procurement of test materials such as blank packaging materials, etc for equipment testing during vendors Factory Acceptance Tests (FATs) and on-site commissioning and qualification testing.
  • Set-up of purchasing and planning systems to ensure raw materials and packaging components are available on time.
  • Start-up of laboratories in advance of production facilities to meet commissioning and qualification testing requirements.

5.0 Conclusion

The user requirements specifications detailed in this document shall be utilized to design the facility and other infrastructure with complete documentation package for the project including cost estimates, project time schedule, etc. for effective implementation, completion and maintenance of the project.  The documentation package shall include additional details if, any required from the point of view of the compliance of regulators requirements over and above the details furnished in this document.  The design personnel of the project, based on the requirements spelled out in this document shall prepare a check list to ensure that all the needs are fulfilled/taken care of while designing and also during preparation of various documents required for the facility.

 

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