National centre for the control and evaluation of medicines - ISS (EN)

The Biologicals and Biotechnologicals Unit carries out vaccine and blood products control activities within the European network of Official Medicines Control Laboratory (OMCL) coordinated by the European Directorate for the Quality of Medicines (EDQM) in a Quality Assurance System, compliant with ISO 17025 standards. The Unit is also a WHO – Contracted Laboratory and adheres to the WHO Global Network for Biologicals. More in details, the following activities are carried out.

Control activities 
The main control activities concern: 

• control of batches of blood products and bacterial/viral vaccines, before their marketing authorisation, with the issue of European Certificates, valid in all Member States of the European Union 
• control of the pools of plasma intended for industrial fractionation for the production of blood products, with the issue of Certificates of approval, valid in all Member States of the European Union 
• execution of specific tests (e.g. MAPREC) on behalf of other OMCLs
• execution of specific tests in the context of the annual drug control program at the national (AIFA) and European (EDQM) level and of relevant analyses, following Pharmacovigilance reporting, carried out on vaccines, blood products and other biological and biotechnological drugs 

Evaluation activities 
The main evaluation activities concern: 

• evaluation of the Quality part of the dossier for the purpose of the Marketing Authorization (MA) – or for variations of the MA – of vaccines, blood products and other biological and biotechnological drugs as well as of gene therapy both at the national level (National procedures) and at the European level (centralised, decentralised and mutual recognition procedures)
• evaluation of dossier of Plasma Master Files as part of their certification, both at a national level in collaboration with the Italian Medicines Agency and the National Blood Centre (AIFA certification), and at the European level (European Medicines Agency certification)
• evaluation of the dossiers submitted for the authorization for Phase I clinical trials (DPR 439/2001, Legislative Decree 211/2003 and Legislative Decree 200/2007), with respect to quality and viral safety of biological/biotechnologicals drugs and for gene therapy
• evaluation of dossiers for national and centralised Scientific Advice and Protocol Assistance procedures, exclusively for quality aspects, aimed at providing technical opinions in order to facilitate the development of high quality biological and biotechnological drugs for the benefit of patients

In addition to the main control and evaluation activities listed above, the following activities are also carried out in the Unit:

• elaboration of European Pharmacopoeia monographs through participation in the work of expert groups
• participation in national and international commissions and working groups
• development of guidelines and related documents through participation in the respective drafting groups, both nationally and at the European level 
• Good Manufacturing Practice (GMP) inspections at manufacturing facilities 
• research applied to the development and standardization of analytical methods aimed at evaluating the quality and safety of biological and biotechnological drugs and for advanced therapies 
• research applied to the development of alternatives to in vivo tests 
• validation of reference preparations for vaccines
• research applied to the development of innovative methodologies for the evaluation of blood products
• research applied to the development of new methodologies for the diagnosis of hereditary anemia by thermogravimetry and associated with chemometrics 
• diagnosis of hereditary hemolytic anemia due to enzyme and red cell membrane defect
• production of reference preparations for blood centres to be used in serological and molecular tests for blood donor qualification 
• organization of external quality assessment studies (VEQ) for serological and molecular tests

Unit organization 
The organization of the activity is in the context of the ISO 17025 and ISO 9001 standards. The Unit is organized in eight sections, four dedicated to the control of vaccines and blood products, three to other biologicals/biotechnologicals and to gene therapy products and one is dedicated to statistics. There is also an evaluation section that operates across the different sections, depending on the specific skills of the Unit staff. Each section is assigned a coordinator responsible for the respective activities.

Blood products 1 Section  (EMO-1) 
Coordinator: Dr. Karen Cristiano 

Control and evaluation activities 

• evaluation and control of immunoglobulins for human use, normal and hyperimmune, intended both for the national/EU market, through the framework of the OCABR (Batch Release), and for the foreign non-EU market (Testing certificate) 
• control and certification of plasma pools to be used for the production of blood products for human use, carried out within the framework of the OCABR 
• Post-marketing surveillance of immunoglobulins in the context of the AIFA Annual Control Program (PCA) 
• evaluation of Plasma Master File (PMF) dossiers, for the purpose of their national and European certification, to ensure the quality and safety of the plasma intended for the production of blood products for human use 
• evaluation and control activities related to the defectiveness of immunoglobulins for human use and to their adverse reactions 
• evaluation of dossiers of immunoglobulins for human use, with respect to quality and adventitious agents safety, for the purpose of their Marketing Authorisation (MA) through national and European procedures (mutual recognition, decentralized and centralized) 
• evaluation of variations in the MA dossiers of immunoglobulins for human use, with respect to quality and adventitious agents safety, through national and European procedures (mutual recognition, decentralized and centralized)
• evaluation of dossiers of investigational medicinal products, with respect to adventitious agents safety of biologicals/biotechnologicals, submitted for the authorization of Phase I clinical trials (Decree of the President of the Republic 439/2001, Legislative Decree 211/2003 and Legislative Decree 200/2007)
• technical-scientific assessments in the areas of competence after evaluation of the respective documentation

Research activities 

• participation in international collaborative studies aimed at defining new reference standards or preparations to be used for viral nucleic acid detection  by NAT and for immunobiological assays 
• development and standardization of analytical methods, with particular reference to NAT methods, through participation in international collaborative studies 
• development and distribution of reference preparations calibrated in International Units, to be used in NAT methods for HCV, HIV and HBV
• organization of External Quality Assessment studies (EQA) for NAT methods applied to viral genomes (HCV, HIV and HBV). The results of these studies find application in the field of screening and control of blood products 

Other activities 

• participation in the works of national and international bodies, i.e EMA, OMCL Network, Groups 6 and 6B of the European Pharmacopoeia 
• drafting of monographs in connection with the participation in the works of Groups 6 and 6B of the European Pharmacopoeia 
• participation in the drafting of EMA guidelines concerning the PMF 

Blood products section 2 (EMO-2) 
Coordinator: Dr. Patrizia Caprari 

Control and evaluation activities 

• evaluation and control of albumins, clotting factor concentrates (FVIII, FIX, prothrombin complex), antithrombin III, fibrin glue and inactivated human plasma, intended both for the national and the European market within the framework of the OCABR (Batch Release) 
• post-Marketing surveillance of blood and heparin products in the context of the AIFA Annual Control Program (PCA) 
• pharmacosurveillance upon reports of ineffectiveness or adverse reactions related to blood and heparin products 
• technical-scientific assessments in the areas of competence after evaluation of the respective documentation

Research and diagnostic activities 

• development of innovative methodologies for the evaluation of blood products 
• diagnostics and pathophysiology of hereditary hemolytic anemias linked to intrinsic red blood cell defects, through the study of genetic, molecular and biochemical factors that underlie G6PD deficiency, hereditary spherocytosis and hereditary elliptocytosis 
• new methodologies for the diagnosis of hereditary anemia: thermogravimetry associated with chemometrics 
• screening of blood donors for the presence of glucose-6-phosphate dehydrogenase deficiency and spherocytosis 
• evaluation of the storage lesion of red blood cells carrying congenital defects of the red blood cell: enzyme deficiency of glucose-6-phosphate dehydrogenase and spherocytic trait 
• study of hemorheological alterations in hereditary anemias: thalassemia, sickle cell anemia, spherocytosis and hereditary elliptocytosis 
• study of hemorheological profiles in the setting of acute infarction 
• consultancy, upon request of hospitals of the National Health Service, for the diagnosis of hereditary anemias that are included among rare diseases (Ministerial Decree 18/05/2001 no. 279): anemias from erythrocytic enzyme defects (glucose-6-phosphate dehydrogenase deficiency G6PD, pyruvate kinase and hexokinase) and erythrocyte membrane defect anemias (hereditary spherocytosis and elliptocytosis)

Bacterial vaccines section (VAC-B) 
Coordinator: Dr. Christina Von Hunolstein 

Evaluation and control activities 

• evaluation and control of the composition of bacterial vaccines for human use (anti-tetanus, anti-diphtheria, anti-pertussis, anti-Haemophilus influenzae, anti-meningococcal, anti-pneumococcal vaccines, etc.) intended both for the national/EU market, within the framework of the OCABR (Batch Release), and for the foreign non-EU market (Testing Certificate) 
• assessment and control of the composition of bacterial vaccines for human use in the context of the AIFA Annual Control Program (PCA) 
• evaluation control activities related to the defectiveness of bacterial vaccines for human use and to their adverse reactions
• evaluation of dossiers of bacterial vaccines or other medicinal products of bacterial origin (e.g. live biotherapeutic products, bacterial lysates, homeopathics of bacterial origin), with respect to the quality aspects, for the purpose of their Marketing Authorisation (MA) through national and European procedures (mutual recognition, decentralized and centralized) 
• evaluation of variations in the MA dossiers of bacterial vaccines and other medicines of bacterial origin , through national and mutual recognition procedures 
• participation in the works of national and international bodies, i.e. ISS Animal Welfare Organization, OMCL netork, Group 15 of the European Pharmacopeia, Live Biotherapeutic Working Party of the European Pharmacopeia, OCABR Drafting Group for Vaccines of the OMCL Network, WHO Global Network for Biologicals, European Network OPINION 
• drafting of monographs related to the participation in the works of the Expert Group 15 and of the Working Group for Live Biotherapeutic Products of the European Pharmacopoeia 
• drafting of guidelines either related to the participation in the works of the OCABR Drafting Group of the OMCL Network or for EMA and AIFA
• experimental evaluation of analytical methods for the European Pharmacopoeia and for the WHO 
• training analytical methods on behalf of the WHO 

Research activities

• development and validation of methods used in bacterial vaccine control activities
• development and/or validation of alternative methods aimed at reducing the use of animals in Pharmacopoeia tests (Vac2Vac project, BSP104, ECVAM, etc.) 
• participation in collaborative studies for European and international preparations and reference standards 

Viral vaccines Section (VAC-V) 
Coordinator: Dr. Cristiana Chelucci

Evaluation and control activities 

• evaluation and control of the composition of seasonal and pandemic influenza vaccines and varicella vaccines intended both for the national / EU market, carried out within the framework of the OCABR (Batch Release), and for the foreign-non-EU market (Testing Certificate) 
• evaluation and control of the composition of hepatitis A vaccines intended for the non-EU foreign market (Testing Certificate) 
• evaluation and control of the composition of viral vaccines (flu vaccine, inactivated Salk polio vaccine, varicella vaccine, measles-mumps-rubella vaccine, papilloma vaccine, anti-rotavirus vaccine, hepatitis A vaccine, hepatitis vaccine) within the AIFA PCA 
• execution of the MAPREC assay to evaluate the percentage of neurovirulent revertants in the mother suspensions of polio vaccine 
• evaluation and control activities related to the defectiveness of viral vaccines for human use and adverse reactions 
• evalutation of dossiers (Quality) of vaccines for human use for the purpose of their Marketing Authorisation through national and European procedures (mutual recognition, decentralized and centralized) 
• technical advice on viral vaccines 
• participation in the work of national and international bodies: EMEA, OMCL Network 
• participation in European collaborative studies for the calibration of reference preparations for viral vaccines 

Research activities

• participation in international or European collaborative studies aimed at defining new reference standards or preparations to be used for potency assays for viral vaccines 
• validation of analytical methods for vaccine control 

Biological Section (BIO) 
Coordinator: Dr. Raffaella Tinghino 

Evaluation and control activities 

• evaluation activities of the registration dossiers concerning the quality aspects of biological drugs for human use (for example: allergens, urinary derivatives, heparins, homeopathic products, herbal drugs, etc.), in the context of national procedures (Authorizations for the in Commerce, AIC or Variations of the AIC) and European (Mutual Recognition, Decentralized and Centralized) 
• evaluation of dossiers of investigational medicinal products, with respect to the quality aspects of biologicals/biotechnologicals, submitted for the authorization of Phase I clinical trials (Decree of the President of the Republic 439/2001, Legislative Decree 211/2003 and Legislative Decree 200/2007)
• evaluation and analysis upon Pharmacosurveillance reports from AIFA  

Research activities 

• research aimed at the development and validation of analytical methods for evaluating the quality of diagnostic and immunotherapeutic extracts used in the treatment of allergic diseases 
• participation in international collaborative studies aimed at defining reference preparations and validation of ELISA tests, to be used for the standardization of allergenic extracts used for diagnosis and immunotherapy 

Other activities 

• participation in the drafting of EMA guidelines concerning the quality of biologicals 
• participation in the drafting of monographs of the European Pharmacopoeia for allergens 
• participation in national and international commissions and working groups in relation to allergologic problems, management of the database of sensitizing chemicals (BDS)  in collaboration with the National Centre for Chemicals, Cosmetics and Consumer Protection and with the IT sector of the Italian National Institute of Health
• teaching in the context of the Asthma and Allergies Project: the toolbox, promoted by the Lazio Association for Asthma and Allergic Diseases, regarding the indoor air quality in schools, information on health risks and prevention methods 

Biotechnology Section (BT) 
Coordinator: Dr. Francesca Luciani 

Evaluation and control activities 

• evaluation of the quality aspects of dossiers of biotechnologicals, and related variations, for the purpose of their Marketing Authorisation through centralized procedures, on behalf of AIFA, where Italy acts as Rapporteur, Co-Rapporteur or Peer Reviewer
• assessment ctivities for the quality of biotechnologicals in the context of European scientific advice/protocol assistance (EMA) procedures, upon request from AIFA
• post-marketing surveillance for biotechnologicals authorized through the centralized procedure (CAP) organized by the European Medicines Agency (EMA) and the European Directorate for the Quality of Medicines (EDQM). The section, in particular, tests the potency and purity of biotechnologicals by immunoassay (ELISA), bioassay (on cell cultures), flow cytometry (FACS), chromatographic methods (HPLC/UPLC) and capillary electrophoresis (CE-SDS and cIEF) 
• evaluation and control activities related to the defectiveness of biotechnological products for human use and adverse reactions, and in the context of counterfeiting activities 
• evaluation of dossiers of investigational medicinal products, with respect to quality and adventitious agents safety of biotechnologicals, submitted for the authorization of Phase I clinical trials (Decree of the President of the Republic 439/2001, Legislative Decree 211/2003 and Legislative Decree 200/2007)

Research activities 

• participation in international collaborative studies aimed at defining new standards and reference preparations for biotechnologicals. Development and standardization of analytical methods for the molecular and functional characterization of monoclonal antibodies
• development and standardization of: 
  • bioassay (in vitro) for the determination of the potency of biotechnologicals 
  • chromatographic methods (HPLC/UPLC) for the purity control of biotechnologicals 
  • capillary electrophoresis methods (CE-SDS and cIEF) for the purity control of biotechnologicals 
• transfer, standardization and application of methods for the control of biotechnologicals 
• participation in the activities organized and coordinated by the EDQM within the MAB Working Party and the OMCL Monoclonal Antibodies Testing Group aimed at identifying and harmonizing the control methods and reference materials for the control of medicinal products containing monoclonal antibodies in the EU 
• participation in international collaborative studies aimed at defining standard analytical methods to be used for the control of biotechnologicals

Other activities 

• participation in the works of national and international bodies, i.e. EMA Biologics Working Party (BWP), OMCL Network, Group 6, MAB Working Party, OMCL Mab testing group 
• participation in the drafting of EMA guidelines concerning the quality of biotechnologicals 
• participation in the drafting of monographs and general chapters of the European Pharmacopoeia concerning biotechnologicals 

Gene Therapy Section (TG) 
Coordinator: Dr. Filomena Nappi 
 
Evaluation and control activities 

• evaluation of dossiers of investigational medicinal products, with respect to quality and adventitious agents safety of drugs for advanced therapies, submitted for the authorization of Phase I clinical trials (Decree of the President of the Republic 439/2001, Legislative Decree 211/2003 and Legislative Decree 200/2007)
• participation in activities in support of technical-scientific commissions at international bodies 

Research activities

• participation in the activities organized and coordinated by the OMCL EDQM Gene Therapy Working Group aimed at identifying and harmonizing the control methods and reference materials for the control of gene therapy products in the EU
• participation in collaborative studies aimed at defining new standards or reference preparations for gene therapy products 
• participation in collaborative studies for the development and validation of analytical methods for the control of drugs for gene therapy 

Other activities 

• participation in the elaboration and revision of texts of the European Pharmacopoeia concerning gene therapy topics 

Statistical section 
Coordinator: Dr. Andrea Gaggioli 

Activities

• participation and support/advice in various control, evaluation and research activities carried out by the different sections of the Department 
• participation in international working groups 
• drafting of guidelines and related documents through participation in the respective drafting groups in Europe 
• development of calculation and data processing models 
• technical-scientific assessments and reports 

Control activity 
The main control activities concern: 

• National Post Marketing Surveillance (Annual Medicinal Composition Control Program, PCA) 
• control activities related to defective medicines, presence of foreign bodies, ineffectiveness and adverse reactions 
• control activities related to non-conformities found during the GMP inspection phase 
• European Post Marketing surveillance (CAP, quality control of medicines approved with Centralized Procedure) 
• Market Surveillance Studies (MSS), European multilateral studies carried out in order to ensure that the same types of medicines are of comparable quality in the different Member States 
• control activities on falsified medicines 
• activities on illegal medicines and medicines in disguise, food supplements, medical devices and cosmetics adulterated by addition of pharmaceutical active substance 

Evaluation activities 
The main evaluation activities concern: 

• assessment of the quality part of dossiers submitted for the the Marketing Authorisation of chemical medicinal products  both at national (marketing authorization and variations) and at European level (centralized, decentralized and mutual recognition procedures) 
• assessment of the quality part of dossiers submitted for the  authorization of Phase 1 (Comma C), Phase 2 and Phase 3 clinical trials  of investigational chemical medicinal products 
• assessment of the quality part of dossiers for Marketing Authorisation of chemical medicinal products intended for veterinary use  national and European decentralized procedures 
• ad hoc assessments on European guidelines
•  scientific advices on chemical medicinal products

In addition to the main control and evaluation activities listed above, the following activities are also carried out in the department: 

• elaboration of European Pharmacopoeia monographs through participation in the works of expert groups 
• coordination of control activities related to the European network of Official Medicines Control Laboratories (OMCL/EDQM), relating to chemical drugs for human use
• participation in European collaborative studies for the definition of reference chemicals (CRS) 
• participation in national and international commissions and working groups
• inspection activities to verify compliance with the standards of good manufacturing practice (GMP) at pharmaceutical facilities 
• applied research 

Unit organization  
Organization of the activity under the ISO 17025 and ISO 9001 Standards 

The activity of the Unit is organized into six sections, three dedicated to control activities, two to evaluation activities and one to statistical data processing. For the control activity, the staff is involved in laboratory activities; the assessment activity operates across the different sections, depending on the specific skills of the Unit staff. Each section is assigned a coordinator who constitutes the entry channel for specific problems and has the task of coordinating activities based on his scientific competence in the specific area. 

Control activities 
Pharmacosurveillance Section 1 (FS1)
Coordinator: Anna Borioni 

• National Post Marketing Surveillance (PCA) 
• European Post Marketing Surveillance (CAP) 
• Market Surveillance Studies (MSS) 

Pharmacosurveillance Section 2 (FS2) 
Coordinator: Monica Bartolomei 

• defectiveness of medicines, presence of foreign bodies 
• ineffectiveness and adverse reactions 
• GMP non-compliance 

Anti-f Section (AF) 
Coordinator: Monica Bartolomei 

• pharmaceutical falsification
• falsification of food supplements, medical devices and cosmetics 

Evaluation activities 
Evaluation Section 1 (VAL1) 
Coordinator: Rosella Ferretti 

• national procedures (Marketing Authorisation and variations) 
• european procedures (centralized, decentralized and mutual recognition) 

Evaluation Section 2 (VAL2) 
Coordinator: Rosella Ferretti 

• phase 1 clinical trials Phase 2 and Phase 3 clinical trials 

Statistics  
Section (FC-STAT) 
Coordinator: Andrea Luca Rodomonte 

• statistical calculations 
• validation protocols 

Research activities 
The main themes of the research are listed below: 

• study of the parameters that influence the quality of chemical drugs 
• development and validation of analytical methods for drug quality control
• development and validation of HPLC methods for the analysis of chiral drugs
• development and validation of screening methods for the analysis of falsified drugs and analysis of suspect samples 
• development and validation of screening methods for the analysis of “medicines in disguise”,  namely food supplements,  medical devices and cosmetics adulterated by illegal addition of active pharmaceutical ingredients, and analysis of suspect samples 
• development of analytical methods for the evaluation of the quality of herbal substances or plant preparations and for the study of their metabolic profile 
• study of problematic issues related to the similarity of generic/equivalent drugs 
• study of the structural characteristics and aggregation mechanisms of peptide drugs and their influence on the efficacy and safety of the drug 
• study of the solid-state properties of medicinal products of consolidated use 
• development and application of nuclear magnetic resonance techniques in structure identification and purity evaluation of phamaceuticals ingredients 
• synthesis of analytical standards for the control of legal and falsified medicinal products and food supplements 
• critical review of the guidelines and literature concerning the evaluation of measurements uncertainty applied to analytical methods 
• statistical studies applied to the transferability of external analytical methods to the institutional control activity of CNCF

Future developments 
In order to increase public health protection, the Unit activities will be strongly oriented not only towards maintaining current skills within the OMCL network, but also to strengthening some activities regarding emerging problems, in particular those related to the falsification of medicines and other products of health interest, both nationally and internationally. 

Organization of the laboratory 
The laboratory is organized into 3 sectors in which the staff operates on the basis of their skills. 
Pharmaceutical technique laboratory 

• disaggregation test for  tablets and capsules 
• dissolution test for oral solid pharmaceutical forms 
• friability of uncoated tablets 
• resistance to crushing of tablets 

Analytical chemistry laboratory 

The analytical chemistry laboratory includes: 

Chromatography 

• liquid chromatography (HPLC, UPLC, FPLC) 
• gas chromatography (GC / FID) 
• thin layer chromatography (TLC) 

Spectroscopy 

• UV / Vis spectrophotometry 
• infrared spectrometry (FT-IR) 
• nuclear magnetic resonance spectrometry (NMR) 
• mass spectrometry (MS) 

Potentiometry 

• pH determination 
• titrations 
• semi-micro determination of water (Karl Fischer) 

Coulometry 

• micro water determination (Karl Fisher) 

Thermal Analysis 

• differential scanning calorimetry (DSC) 
• thermogravimetry (TGA) 
• melting point (capillary method) 

Volumetric analysis  

• titrations with indicator 

Polarimetry 

• optical rotation 

Densitometry 

• relative density of liquids 

Organic chemistry laboratory  

• Synthesis and purification of organic molecules of pharmaceutical interest