Large, technologically advanced production site, dedicated to manufacturing,
primary and secondary packaging of oral solids and liquids.
Production Unit 1
This unit, covering a global area of about 360 sqm, was built at the beginning of the 80s and completely renewed in year 2004.
It includes the following equipment:
• a loading hopper for pre-weighted ingredients
• Intermediate Containers for powders (IBC)
• 1 400-liter Diosna granulator
• 1 Aeromatic T6 fluid-bed drier
• 1 1000-liter ribbon mixer
• 1 vacuum system for transferring milled granulate
• 1 double-station Fette 3090 compressing machine
• a washing area and areas for storage of dirty/clean spare parts
Production Unit 2
Completed in year 2002, Unit 1 is built on three levels for a global covered area of about 12.700 sqm.
The dispensing area for raw materials is located on the 3rd level; wet-granulation and dry-mixing areas occupy the 2nd one, while the 1st floor houses the compression and film-coating areas.
At level 3, the raw materials delivered by warehouse (active ingredients and excipients) are dispensed in dedicated Containers (IBC) through an integrated material handling system.
Five dispensing stations provide automatically dispensing of high volumes ingredients through weight- loss measuring devices .
Two laminar-flow cabinets (Extract Technology) are also present for the manual dispensing of medium/low volumes of pre-weighted ingredients.
The whole plant is equipped with human/machine interfaces (HMI) and validated bar-code reading systems, guiding the operators during the production steps and performing the double check function at the same time.
The above dispensing area also includes adequate technical spare areas, for future expansion.
Once the ingredients delivery in the IBCs is completed, the batches/sub-batches hereby contained can be moved to the following processing areas by two laser-guided vehicles (AGV),
The wet granulation module Hi-Shear is equipped with a 600-liter Diosna granulator, coupled with two T8 Niro Aeromatic fluid-bed driers.
The module is completely automatic and controlled by the operators through a Human/Machine Interface (HMI).
The granulator load ranges from 150 to 220 kg; the two driers can work in parallel to optimize process cycles.
The module is equipped with a Cleaning in Place (CIP) system.
Dry mixing (Direct Compression)
The dry mixing can be directly made in the IBCs, by using a column mixer; the same system is also used for the lubrication of IBCs coming from the wet granulation module.
Alternatively, a module equipped with a 2200-liter ribbon mixer able to mix batches ranging from 450 a 1.000 kg can also be used.
Such module, totally automatic and controlled by HMIs, feeds a double exit Fette 3090 compressing machine by gravity.
Each of the manufacturing plant’s three levels is equipped with dedicated washing areas,
with stainless steel sinks, automatic washing machines and storage areas for both dirty and clean equipment. The segregationbetween clean/dirty areas is supported by a suitable cascading pressures system where the containment is achieved by means of a negative pressure gradient from the cleanest to the dirtiest areas.
The compression area is equipped with automatic Fette (3090 double-station and 2090 single-station) compressing machines.
All the compressing machines are installed inside dedicated booths equipped with pharmaceutical-grade separators minimizing the direct contact between operator and product as well as reducing the noise in the work environment.
Each compressing machine is equipped with a check master (automatic robot for the execution and data collection from “in process” controls relative to dust extractors and metal detectors).
The coating area is equipped with two Manesty Premiere perforated-drum coating machines. Both coaters are controlled by dedicated HMIs and can operate with loads ranging from 200 to 600 kg tablets.
Production Unit for oral liquids
This unit covers a total area of about 500 sqm and has been designed in such a way to assure an adequate separation of flows among operators, manufacturing/packaging materials and finished products.
This Unit includes a dispensing area, equipped with a suitable cabinet for raw materials classified as OEB 4, where pre-solubilisation of the active substance in the diluting solvent can be performed.
Two separate preparation areas are present, each one equipped with a preparation tank, a storage tank, transfer pumps and filtration units; both preparation areas are connected with the primary/secondary packaging line.
The primary packaging consists of the following machines: blowing machine, capsules loading machine and filling machine.
The secondary packaging consists of the following machines: buffer n.1, labelling machine for the vials, buffer n°2, boxing machine, labelling machine for the boxes, scales and cartooning machine.
The centralized Utility building, is able to supply hot water, steam, refrigerated water and compressed air to the entire plant through the following equipment:
• 3 Boilers for the production of clean steam: 2, 4 and 6 t / h
• 4 Compressors for the production of filtered air: 16, 37, 90 and 132 kW
• 4 interconnected electric substations: 800, 1600, 2500 kVA
• Integrated fluids distribution network
• a program of energy efficiency is active in the plant since year 2004
• consumptions are continuously monitored through a granular measurement system (Energy Sentinel)
• an about 1000 sqm large portion of the roof cover has been equipped with a photovoltaic system, able to absorb about 7% of the total energy consumption.
• the creation of a co-generation system (combined generation of Electric and Thermal Energy) empowering the whole site is actually in progress.
Purified Water Production System
The system for the production of purified water (Siemens) supplies <1,1μ deionised water by a sanitized (80 °C) continuous cycle to Production Unit 2 and by an environmental loop to the remaining areas of the plant.
Warehouses and packaging
The delivery of the components to the packaging lines is managed by an automatic materials handling system (Material Handling Control System) integrated with the high-density warehouses (HBS). The components are moved by automatic laser-guided vehicles (AGV) and transferred to dedicated pallet slots, located close to each packaging lines.
Two high-density warehouses (HBS) give the site a total storage capacity of 10.300 pallet slots, sub-divided as follows:
• WH 1 - 7,400 slots
• WH 2 - 2.900 slots
The warehouses are totally segregated and are served s by automatic lifters and conveyors; access to these areas is not allowed to the personnel.
The warehouses are controlled for both temperature and relative humidity and the critical parameters are continuously monitored.
The packaging area, which covers a total area of about 3.700 sqm, is equipped with 11 Marchesini lines totally integrated with the materials handling system (MHCS).
All the packaging lines have been recently modified to guarantee physical segregation among primary and secondary packaging lines, with dedicated flows for operators and materials and suitable differential pressure gradients among different areas.
The lines are equipped for Directive 2011/62/EU -“Falsified Medicine Directive”, by installation of suitable printing and data matrix reading systems and tamper-evident seals, in line with the timeframes imposed by the European Commission.
Compliance, Quality, Safety and respect for the Environment
The company Management is responsible for providing adequate resources and a continuous supervision in order to assure that the final dosage forms of the pharmaceutical products satisfy customers’ expectations about high quality standards and comply with the regulatory requirements in force.
At the same time, the company Management commits itself to achieve excellence in its employees’ Health and Safety stand as well as for the Environment we operate in ; this Policy is transferred to all employees as well,
In line with ICH Q8, Q9 e Q10, Quality and Compliance are considered a competitive advantage and are based on two basic pillars:
A state of Permanent Preparation for Audits, making all the employees feeling directly involved and responsible for the Quality Systems of their pertinence:
The Quality Assurance is responsible for ensuring that adequate Quality Systems are in place to guarantee that manufacturing, packaging, control, storage and distribution of products are performed in compliance with cGMP and all relevant regulatory requirements
The company Management is responsible for providing adequate resources and supervision in order to satisfy customers’ expectations about high quality standards of products
The Functional Areas are responsible for the creation and maintenance of a working environment able to guarantee that quality, compliance to regulations, safety and environment are of primary importance in all the activities performed
The Lean Quality approach, where Compliance results both effective and efficient thanks to the integration of the Lean (e.g. 5S, Right First Time, Visual Factory, Continuous Improvement) and Quality Risk Management principles with the Quality by Design criteria.
The Quality Control consists of a chemical lab, a microbiological lab and a lab for packaging materials control.
The QC analyses and approves all the raw materials and packaging materials, performs the environmental controls, tests the finished product for authorizing the release. All the finished products arriving form extra-European countries are tested for authorizing the Import according to the regulations in force.
The list of the equipment includes air samplers, autoclaves, dissolution baths, freezers, gas-chromatographers, HPLC systems, laminar-flow cabinets, microscopes with camera and printer, ovens, particle-size analysers, fridges, spectrophotometers (IR, NIR, UV/Visible), Total Organic Carbon analyser and Verification System for printed bar codes.
The manufacturing plant covers a total area of about 5000 sqm.
EQUIPMENT AND PRODUCTION CAPACITY
Yearly capacity is conventionally calculated on a single work shift x 5 days:
(injectable products aseptically manufactured and terminally sterilised)
(injectable products aseptically manufactured and terminally sterilised)
0,5 ml 10 ml → 10.000.000
List of APIs processed in the plant:
Sodium Clodronate tetrahydrate
Dexamethasone Sodium Phosphate
Class III Medical Devices
2 ml and 4 ml → 350.000
Different possible data relative to the site productive capacity can be calculated in case a 2x5 organisation is implemented.
All the persons working in the plant are highly qualified and trained in all the production activities involving both aseptic processes and terminal sterilisation.
The Water for Injection is obtained by distillation of the Purified Water by a stainless steel triple distiller able to produce about 120 litres/hour. The plant for the production and storage of water for injection is equipped with an AISI 316 L stainless steel recirculation system, which keeps the produced water in movement at a 70°C temperature. The system is totally automatically managed and controlled.
• N° 1 60 Kg stainless steel Blender
• N° 1 140 Kg stainless steel Blender
• N° 1 Filling and Closing Machine for ampoules Rota
• N° 1 Filling and Closing Machine for prefilled syringes
Oven and autoclave
• N° 2 Inspection Machines for ampoules
• N° 1 Leak Test Machine for the ampoules integrity test
N° 1: Packaging line for ampoules
N° 1: Packaging line for prefilled syringes
QUALITY ASSURANCE AND QUALITY CONTROL
Our Quality Operations Department focuses on assuring compliance with all needed quality standards in order to grant full compliance to cGMP and all relevant regulations about manufacturing, packaging, chemical-physical, microbiological testing and distribution activities.
Our Quality Control Department consists of a chemical-physical and a microbiological lab, analysing incoming raw materials and primary and secondary packaging materials, performing environmental controls and testing finished products to authorise batch release.
Manufacturing Authorisation aM - 30/2019
GMP Certificate N° IT/56/H/2019