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Cell therapies and quality level in Cell Factories for Pharma
Procelltech was born in 2009 and has established itsoffices and GMP laboratories (250 m2) in the BioindustryPark Silvano Fumero, close to University and internationalPharma companies.
Procelltech is member of bioPmed, the new Italianinnovation cluster dedicated to bio and medicaltechnologies that gathers around 60 companies, researchcentres and three academic institutions (Università di Torino,Università del Piemonte Orientale and the Politecnico diTorino)
Procelltech’s activities are aimed to sustain public andprivate institutes in clinical and R&D Research field and isrecognized in BioInItaly Reports (2010-2011) issued byEarns & Young and Assobiotech as one of the 320 ItalianCompanies performing R&D activities in the red biotechenvironment.
How Stem Cells Are Changing the Way We Think About DiseaseTime Magazine_ Mar. 17, 2011
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Regenerative medicine is an emerging clinical disciplinethat aims to employ cellular medicines to restore thefunctions of damaged or defective tissues and organs(Trounson A., 2008)
a personalized medicine/point of contact model, in which cells are harvested from the same or a related individual and undergo minimal or extensive manipulation before being delivered to the recipient;
a banking model, akin to the existing umbilical-cord blood system and involving indeterminate periods of storage and minimal processing;
a manufacturing model, whereby cells are extensively manipulated and produced in a central facility and a single lot is used for a single or relatively large number of patients, as in existing drug delivery paradigms.
Part I – Basic Requirements for Medicinal ProductsChapter 1 Quality Management (revision February 2008)Chapter 2 PersonnelChapter 3 Premise and EquipmentChapter 4 Documentation _Coming into operation 30 June 2011Chapter 5 ProductionChapter 6 Quality ControlChapter 7 Contract Manufacture and AnalysisChapter 8 Complaints and Product RecallChapter 9 Self Inspection
Part II – Basic Requirements for Active Substances used as Starting MaterialsBasic requirements for active substances used as starting materials
Part III - GMP related documentsSite Master FileQ9 Quality Risk ManagementQ10 Note for Guidance on Pharmaceutical Quality SystemMRA Batch Certificate19
Annex 1 Manufacture of Sterile Medicinal ProductsAnnex 2 Manufacture of Biological Medicinal Products for Human UseAnnex 3 Manufacture of RadiopharmaceuticalsAnnex 4 Manufacture of Veterinary Medicinal Products other than Immunological
Veterinary Medicinal ProductsAnnex 5 Manufacture of Immunological Veterinary Medicinal ProductsAnnex 6 Manufacture of Medicinal GasesAnnex 7 Manufacture of Herbal Medicinal ProductsAnnex 8 Sampling of Starting and Packaging MaterialsAnnex 9 Manufacture of Liquids, Creams and OintmentsAnnex 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for InhalationAnnex 11 Computerized Systems (revision January 2011) Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal ProductsAnnex 13 Manufacture of Investigational Medicinal ProductsAnnex 14 Manufacture of Products derived from Human Blood or Human Plasma (May
2011)Annex 15 Qualification and validationAnnex 16 Certification by a Qualified person and Batch ReleaseAnnex 17 Parametric ReleaseAnnex 19 Reference and Retention Samples
Eudralex vol. 4_Annex 1Manufacture of Sterile Medicinal Products
The manufacture of sterile products should be carried out in cleanareas entry to which should be through airlocks for personneland/or for equipment and materials. Clean areas should bemaintained to an appropriate cleanliness standard and suppliedwith air which has passed through filters of an appropriateefficiency.The various operations of component preparation, productpreparation and filling should be carried out in separate areaswithin the clean area. Manufacturing operations are divided intotwo categories; firstly those where the product is terminallysterilized, and secondly those which are conducted aseptically atsome or all stages.Clean areas for the manufacture of sterile products are classifiedaccording to the required characteristics of the environment. Eachmanufacturing operation requires an appropriate environmentalcleanliness level in the operational state in order to minimize therisks of particulate or microbial contamination of the product ormaterials being handled.
For the manufacture of sterile medicinal products 4 grades can be distinguished.
Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections.Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone.Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.
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Eudralex vol. 4_Annex 1 (II)Manufacture of Sterile Medicinal Products
The production of biological medicinal products involves biological processes and materials, such as cultivation of cells or extraction of material from living organisms. These biological processes may display inherent variability, so that the range and nature of by-products are variable.
Control of biological medicinal products usually involves biological analytical techniques which have a greater variability than physico-chemical determinations.
In-process controls therefore take on a great importance in the manufacture of biological medicinal products.
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Eudralex vol. 4_Annex 2Manufacture of Biological Medicinal Products for Human Use
Validation: Establishment of evidence in accordance with therules of ”Good Manufacturing Practice” that procedures,processes, items of equipment, materials, operations orsystems do in fact result in the intended outcomes.
Aim To verify if the method is specific for human cell lines (3repetition of the test)
In-house Reference cellular preparation StemPro® HumanAdipose-Derived Stem Cell (Invitrogen) has been compared tothe following non-human cell lines and a bacterial preparation(*):
For all 3 test repetitions, only with the StemPro® cellularpreparation a full STR profile was obtained
DNA profiling validationinterspecie-specificity
(*) Specificity controls have been chosen by analyzing possible non-human contaminants during in-housereference cellular preparation colture(Cell spotted on FTA cards at 100 cells/µl and Bacteria at 100 CFU/µl)
Specificity Assessment of mAbs ability to identify targeted MSCsurface antigens (Dominici M et al., Cytotherapy, 2006) byFluorescence Minus One (FMO) method
7 color staining of StemPro®
MSCFMO controls
MSC markers (CD73, CD105, CD29, CD44 and CD90): highly expressed on cell surface
•MSC and HLSC display a typical MSCs phenotype•Kidney papillar SC do not fulfill all the criteria of classical MSC,CD105 and CD90 are almost absent•HSC express typical Hematopoietic cell markers (CD34 and CD45)and display some of the staminal markers like CD44, CD29 andCD105.
•StemPro® markers in accordance with product specification