Dr.ssa Stefania CislaghiGMP Compliance Executive Consultant, PQE Group

Università di Trieste– 7 Novembre 2020

La qualità in ambito biotecnologico

Agenda

Introduzione personale e dell’azienda PQE

Il processo di Drug Discovery ed il mondo biotech

Le linee guida applicabili all’ambito biotecnologico

Conclusioni

Agenda

Introduzione personale e dell’azienda PQE

Il processo di Drug Discovery ed il mondo biotech

Le linee guida applicabili all’ambito biotecnologico

Conclusioni

Stefania @ a glance

Laurea triennale Biotecnologie BiomedicheLaurea specialistica Biotecnologie Industriali (2009)

Master in Ricerca e Sviluppo Preclinico e Clinico dei farmaci (2012)

Master in Business Administration (2016)

2009 -

2011

2011 - 2020

2020

2020

Dip. BiotecnologieIngegnerizzazione e produzione R&D di proteine ad interesse oncologico

Sviluppo e produzione di farmaci biologici con tecnologie disposableSviluppo metodi analitici Gestione compliance con normative GMP, ICH, ecc.Project Manager sviluppo e industrializzazione ingegnerizzazione cellulare e processi produttiviResponsabile Sviluppo e Produzione Upstream

Senior Lead Auditor presso aziende farmaceutiche (API, prodotti finiti), biotech, materie prime, packaging, eccipienti, medical devices, cosmetiche, aziende distribuzione

GMP Compliance Executive ConsultantGMP compliance e gestione progetti complessi presso aziende farmaceutiche con particolare focus al settore biotech

PQE @ a glancePQE fornisce servizi al mondo farmaceutico da oltre 20 anni

Il portafoglio clienti di PQE vanta al suo interno i maggiori nomi delle industrie farmaceutiche

italiane, europee e mondiali

PQE @ a glance

GxP Compliance

GLP Compliance

GMP API Compliance

GMP FP Compliance

GDP Compliance

GCP compliance

GVP Compliance

Regulatory Affairs

CS Compliance

Audit

GAP Assessment

Risk analysis

GAP Fulfillment

Inspection readiness

Inspection support

Agenda

Introduzione personale e dell’azienda PQE

Il processo di Drug Discovery ed il mondo biotech

Le linee guida applicabili all’ambito biotecnologico

Conclusioni

Il processo di Drug DiscoveryCondizione da

trattareFase R&D Fase Pre-clinica Fase Clinica Fase Commerciale

Condizione clinica

Eziopatogenesi

Centinaia

Migliaia (e oltre)

I/II

I

III

IV

Farmacovigilanza

Farmaco

vigilanza clin

ica

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I farmaci biotecnologiciBiological products are a diverse category of products and are generally large, complex molecules. These products may

be produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell, and are

often more difficult to characterize than small molecule drugs.

The nature of biological products, including the inherent variations that can result from the manufacturing process, can

present challenges in characterizing and manufacturing these products that often do not exist in the development

of small molecule drugs. Slight differences between manufactured lots of the same biological product are normal and

expected within the manufacturing process. (FDA, Biological products definitions)

Linea cellulare Tecniche di DNA ricombinante Selezione clonale Amplificazione in vitro

I farmaci biotecnologici: revenue e sviluppo recente

2019 FDA Drug Approvals,

Nature Reviews Drug Discovery (February 2020)

Sviluppo del processo

produttivo

• Sviluppo upstream

• Sviluppo downstream

• Sviluppo formulazione farmaceutica

• Sviluppo metodi analitici

• Up-scale da scala laboratorio a scala pilota

• Consolidamento del processo e dei metodi analitici

Technology transfer

• Trasferimento dell’intero processo (upstream, downstream, formulation & filling) su scala industriale

• Qualifica/convalida metodi analitici, compresi metodi di rilascio da farmacopea

• convalida E&L, convalida filtrazione sterilizzante, convalide macchine/equipment

• Stesura documentazione a supporto (IFL, SOP, report, ecc.)

Convalida di processo

• Lotti di convalida, caratterizzazione bulk, Purified Product

• Convalida metodi

• Revisione e consolidamento documentazione a supporto (IFL, metodi, SOP ecc.)

• Stesura dossier/SMF/DMF/IND/IMPD ecc. e sottomissione alle autorità regolatorie

Produzione

• Lotti per studio clinico/commercio

• Mantenimento documentazione a supporto

• Ottimizzazione/riconvalida metodi/processo/macchine/equipment

• Revisione/mantenimento documentazione regolatoria

Small molecules manufacturing equipment

Sviluppo linea

cellulare

• Ingegnerizzazione e caratterizzazione della linea cellulare secondo ICH/GMP

• Produzione e caratterizzazione di MCB e WCB

Sviluppo del processo

produttivo

• Sviluppo upstream

• Sviluppo downstream

• Sviluppo formulazione farmaceutica

• Sviluppo metodi analitici

• Up-scale da scala laboratorio a scala pilota

• Consolidamento del processo e dei metodi analitici

Technology transfer

• Trasferimento dell’intero processo (upstream, downstream, formulation & filling) su scala industriale

• Qualifica/convalida metodi analitici, compresi metodi di rilascio da farmacopea

• Convalida virale, convalida E&L, convalida filtrazione sterilizzante, convalide macchine/equipment

• Stesura documentazione a supporto (IFL, SOP, report, ecc.)

Convalida di processo

• Lotti di convalida, caratterizzazione EoPC, bulk, Purified Product

• Convalida metodi

• Revisione e consolidamento documentazione a supporto (IFL, metodi, SOP ecc.)

• Stesura dossier/SMF/DMF/IND/IMPD ecc. e sottomissione alle autorità regolatorie

Produzione

• Lotti per studio clinico/commercio

• Mantenimento documentazione a supporto

• Ottimizzazione/riconvalida metodi/processo/macchine/equipment

• Revisione/mantenimento documentazione regolatoria

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjhlrPcptfhAhWqneAKHeqBBB4QjRx6BAgBEAU&url=https://www.thinglink.com/scene/1090572022309715969&psig=AOvVaw3tVmayw_KgGCIPpng9scPI&ust=1555596506302568https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjhlrPcptfhAhWqneAKHeqBBB4QjRx6BAgBEAU&url=https://www.thinglink.com/scene/1090572022309715969&psig=AOvVaw3tVmayw_KgGCIPpng9scPI&ust=1555596506302568

Sviluppo linea cellulare 1. Ingegnerizzazione linea cellulare

2. Caratterizzazione linea cellulare

3. Produzione e caratterizzazione MCB e WCB

Sviluppo e scale up del processo produttivoUpstream

Downstream

Formulazione farmaceuticaMetodi analitici

Trasferimento del processo su scala industrialeUpstream Downstream

Formulation & fillingMetodi analitici

Da centinaia di ml a litri o decine di litri

Definizione del primary closure system (vial, tappo, ghiera) Consolidamento formulazione farmaceutica su scala industriale

Qualifica/convalida metodi analitici: robustezza, precisione, accuratezza, specificità, LOD, LOQ

Definizione e convalida IPC e metodi di rilascio compresi metodi da farmacopea (es. aspetto, sterilità ecc.)

Da

Convalida e Produzione

GMP

Convalida di processo

Convalida Extractables & Leachables

Convalida di macchine/equipmentDQ,IQ, OQ, PQ, FAT, SAT, URS ecc.

Documentazione a supporto (IFL, SOP, ecc.)

Convalida sistemi computerizzati

Convalida metodi analitici

Convalida cleaning

Agenda

Introduzione personale e dell’azienda PQE

Il processo di Drug Discovery ed il mondo biotech

Le linee guida applicabili all’ambito biotecnologico

Conclusioni

Che cos’è l’Assicurazione Qualità?Linee guida Produzione

farmaci

Linee guida Tossicologia

Linee guida Studi clinici

Linee guida Distribuzione

Linee guida Commercializzazione

Procedure Operative Standard aziendali

Compito dell’Assicurazione Qualità è costruire e garantire costantemente l’aderenza a 360° di tutti i processi aziendali rispetto alle normative applicabili

Si interfaccia con le agenzie regolatorie per tutti i processi che necessitano approvazione/informazione dell’ente normativo

Si interfaccia con tutte le aree aziendali Conduce audit interni ed audit ai fornitori

aziendali

Prepara e segue le ispezioni delle autorità regolatorie

Costruisce e garantisce costantemente che il sistema di Qualità aziendale sia adeguato

Le linee guida WHO, ISPE, IPEC, ISO Annex 3 “Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks”Annex 4 “WHO guidelines for sampling of pharmaceutical products and related materials”

Le farmacopee

EUROPEAN PHARMACOPEIA (Eu-Ph)

UNITED STATES PHARMACOPEIA (USP)

Le linee guida GMP, GLP, GCP, GVP, GxP

The EU legal framework for medicinal products guarantees high standards of quality and safety. It also promotes the functioning of the internal market, with measures that encourage innovation and competiveness in Europe. It is based on the principle that medicinal products may be placed on the market only following a marketing authorisation granted by the competent authorities. A large body of legislation has developed around this principle with the progressive harmonisation of requirements implemented across the whole European Economic Area.Today, medicinal products are authorised at EU level by the European Commission or at national level by the competent authorities of EU countries. Special rules exist for the authorisation of medicinal products for paediatric use, orphan medicines, traditional herbal medicines, vaccines and clinical trials. Once placed on the market, the safety of a medicinal product continues to be monitored throughout its entire lifespan through the EU system of pharmacovigilance.The European Medicines Agency, established in 1995, underpins the centralised authorisation procedure and supports coordination between national competent authorities. The Agency is the hub of a European medicines network comprising over 40 national regulatory authorities guaranteeing a constant exchange and flow of information regarding the scientific assessment of medicinal products in the EU.

https://ec.europa.eu/health/human-use/pharmacovigilance_enhttp://www.ema.europa.eu/

GMP e ambito biotechAnnex 1 Manufacture of Sterile Medicinal Products

Annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use

Type and source of material

Example product

1. Animal or plant sources: non-transgenic

Heparins, insulin, enzymes, proteins, allergen extract, immunosera

2. Virus or bacteria/fermentation/cell culture

Viral or bacterial vaccines; enzymes, proteins

3. Biotechnology -fermentation/cell culture

Recombinant products, MAb, allergens,vaccines

4. Animal sources: transgenic

Recombinant proteins

5. Plant sources: transgenic

Recombinant proteins, vaccines, allergens

6. Human sources Urine derived enzymes, hormones

7. Human sources Products from cells tissues

Starting and raw materials Seed lot and cell bank system Specific operating and quality control principles (ex. sterility tests should be conducted on antibiotic-free cultures […])

Cells or cell banks Specific quality assurance tips (ex. For biological medicinal products with a short shelf life, […] a period of 14 days or less and which need batch certification before completion of all end product quality control tests […]

PART B. SPECIFIC GUIDANCE ON SELECTED PRODUCT TYPESB1. ANIMAL SOURCED PRODUCTSB2. ALLERGEN PRODUCTS B3. ANIMAL IMMUNOSERA PRODUCTSB4. VACCINESB5. RECOMBINANT PRODUCTSB6. MONOCLONAL ANTIBODY PRODUCTSB7. TRANSGENIC ANIMAL PRODUCTSB8. TRANSGENIC PLANT PRODUCTS

Le linee guida ICH

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH's mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. Harmonization is achieved through the development of ICH Guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side.

ICH e ambito biotech

ICH Q5A : Convalida virale

The risk of viral contamination is a feature common to all biotechnology products derived from cell lines. Such contamination could have serious clinical consequences and can arise from the contamination of the source cell lines

themselves (cell substrates) or from adventitious introduction of virus during production.

Three principal, complementary approaches

raw materials, including media components viral testing

assessing the capacity of the production processes to clear infectious viruses

testing the product at appropriate steps of production for absence of

contaminating infectious viruses

Unprocessed bulk and finished product initial and continuous characterization

Richiesta assessment e test aifornitori e scelta di RM caratterizzati

Eventuali test su RM (es. Siero non irraggiato)

Cell line viral characterization Process Viral Clearance study

Cell line viral characterization

MCB WCB Cell Thawing

Day 0

Seed train

Day 10

Production bioreactor

Day 15

Feeding strategy

Day 30

Harvest EoPC

Day 45

Extensive screening for both endogenous and non-endogenous

viral contamination

Endogenous Viruses that may have been undetected in the MCB and WCB.

Further assurance that the production process is not prone to contamination by adventitious viruses

Process viral clearance study

Harvest Affinity step pH adjustment IEX 1 IEX 2 Viral filtrationFinal

formulationTFF 2TFF 1

Categoria derivante dalla linea cellulare e sua caratterizzazione

Best case: solo studi di viral clearance per contaminazioni avventizie(Case A)

Worst case: studi di viral clearance per contaminazioni sia avventizieche endogene, comprese analisi virali su prodotto purificato

(almeno per 3 lotti commerciali)

Come si esegue uno studio di clearance virale

Harvest Affinity step pH adjustment IEX 1 IEX 2 Viral filtrationFinal

formulationTFF 2TFF 1

Presso aziende specializzate (characterized viral banks, safety)

Campioni da processo commerciale o da modello scale down

Scale down validato, assicurare che i campioni siano esattamente paragonabili

Assicurarsi di testare i worst case (es. Se le resine vengono riciclate)

Includere gli adeguati controlli negative (not spyked) e positive (not processed)

Replicati significativi Almeno 4 log di abbattimento virale per almeno 3 o 4

step di processo Calculation of estimated particles per dose

IEX 1

Intermedio di processo

Spyke con quantità nota di virus

Quantificazione virus rimasto

ICH Q5B : rDNA

Characterization of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells.

Expression Construct and Cell Clone Used to Develop the Master Cell Bank (MCB)

Cell Bank System (MCB, WCB)

Limit for In-Vitro Cell Age for Production

Cell line history and production of the cell banks, including methods and reagents used phenotypic and genotypic markers Copy number, insertions or deletions, number of integration sites Protein coding sequence For extrachromosomal expression systems: percent of host cells retaining the expression construct, nucleotide

sequence encoding the product should be verified without further cloning

ICH Q5C : stability tests

Biotechnological/biological products do have distinguishing characteristics to which consideration should be given in any well-defined testing program […] The products are particularly sensitive to environmental factors such as temperature changes, oxidation, light, ionic content, and shear. In order to ensure maintenance of biological activity and to avoid

degradation, stringent conditions for their storage are usually necessary.

5. STABILITY-INDICATING PROFILE

Potency Purity and Molecular Characterisation Visual appearance Sterility (begin and end of storage) Additives or excipients degradation Container/closure systema evaluation

6. STORAGE CONDITIONS

Temperature Humidity Accelerated and Stress Conditions Light Container/Closure Stability after Reconstitution of Freeze-Dried Product

ICH Q5D : cell substrates

Guidance on appropriate standards for the derivation of human and animal cell lines and microbial cells to be used to prepare biotechnological/biological products.

Source, History, and Generation of the Cell Substrate Cell Banking Characterization and Testing of Cell Banks Identity Purity Karyology and Tumorigenicity

Cell Substrate Stability

Consistent production of the intended product

Retention of production capacity during storage

Verifica identità e caratteristiche del prodotto lungo il processo

Verifica mantenimento identità, qualità e resa produttiva durante lo stoccaggio WCB raccolta dati ad ogni lotto MCB almeno ogni 5 anni*

* Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal

products and for the characterization of cell banks (WHO, 2010)

ICH Q5E : comparability

Co

mp

arability

exercise

Evidence that the manufacturing process changes will not have an adverse impact on the quality, safety and efficacy of the drug product.

Take into consideration: The production step where the changes are introduced The potential impact of the changes on the purity as well as on the physicochemical and

biological properties of the product The availability of suitable analytical techniques to detect potential product modifications and

the results of these studies The relationship between quality attributes and safety and efficacy, based on overall nonclinical

and clinical experience.

Quality Aspects to be considered during comparability exercise: Physicochemical Properties Biological Activity Immunochemical Properties Purity, Impurities, and Contaminants Stability

ICH Q5E : comparability exercise results

pre- VS post-change product Comparability assessment Further actions required

Highly similar Comparable None

Appear highly similar, but analytical procedures used are not sufficient to discern relevant differences that can

impact the safety and efficacy of the productNot assessable

Additional testing (e.g., further characterization) or nonclinical and/or clinical

studies to reach a definitive conclusion.

Some differences have been observed in the quality attributes, but it can be justified that no adverse impact on safety or efficacy profiles is expected based on the

manufacturer’s accumulated experience

Comparable None

Some differences have been identified in the comparison of quality attributes and a possible adverse

impact on safety and efficacy profiles cannot be excluded

Probably Not Comparable

Additional data on quality attributes are unlikely to assist in determining comparability. The manufacturer should consider performing

nonclinical and/or clinical studies.

Differences in the quality attributes are so significant that it is determined that the products are not highly

similar and are therefore not comparable. Not comparable

Out of the scope of ICH Q5E.The two products have to be considered

different to each other.

ICH Q6B : Specifiche

Characterization profile for setting up specifications:

Physicochemical properties Biological activity

Animal-based biological assays Cell culture-based biological assays Biochemical assays

Immunochemical properties Purity Impurities Contaminants Quantity/protein content

Adequate In Process Controls to be defined, including acceptance criteria and action limits

Raw materials (ex. Protein A, serum) and excipients adequate specifications should be defined

Appendix for Physicochemical Characterization Structural characterization and confirmation

Amino acid sequence, Amino acid composition, Terminal amino acid

sequence, Peptide map, Sulfhydryl group(s) and disulfide bridges,

Carbohydrate structure

Physicochemical properties

Molecular weight or size, isoform pattern, Extinction coefficient

(REALE!), Electrophoretic patterns, Liquid chromatographic patterns, Spectroscopic profiles

Appendix for Impurities Process related (Cell substrate-derived: DNA, HCP, etc. Cell

culture-derived: antibiotics, serum, etc. Downstream-derived:

guanidine, oxidizing and reducing agents, inorganic salts, solvents

etc.

Product-related impurities (Truncated forms, aggregates,

deamidated, oxidized etc.)

ICH Q6B : SpecificheDrug Substance Appearance and description Identity Purity and impurities Potency Quantity

Drug Product Appearance and description Identity Purity and impurities Potency Quantity General tests (ex. pH and osmolarity) Additional testing for unique dosage forms

Drug Product (Dosage Form; Finished Product)

A pharmaceutical product type that contains a drug

substance, generally, in association with excipients.

Drug Substance (Bulk Material)

The material which is subsequently formulated with

excipients to produce the drug product. It can be

composed of the desired product, product-related

substances, and product- and process-related

impurities. It may also contain excipients including other components such as buffers.

EMA Guidelines on biologics: Active Substances

ICH Q11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) ICH Considerations: oncolytic viruses Allergen products: production and quality issues Development and manufacture of lentiviral vectors Development, production, characterization and specifications for monoclonal antibodies and related products Gene therapy product quality aspects in the production of vectors and genetically modified somatic cells Human cell-based medicinal products Potency testing of cell-based immunotherapy medicinal products for the treatment of cancer Process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission Production and quality control of animal immunoglobins and immunosera for human use Production and quality control of medicinal products derived by recombinant DNA technology Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells Quality of biological active substances produced by stable transgene expression in higher plants Quality of biological active substances produced by transgene expression in animals Quality, preclinical and clinical aspects of gene therapy medicinal products Use of starting materials and intermediates collected from different sources in the manufacturing of non-recombinant biological medicinal products Xenogeneic cell-based medicinal products

Design modifications of gene therapy medicinal products during development In-vitro cultured chondrocyte containing products for cartilage repair of the knee Quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors Stem cell-based medicinal products

DNA and host cell protein impurities, routine testing versus validation studies Use of tumorigenic cells of human origin for the production of biological and biotechnological medicinal products

EMA Guidelines on biologics: Finished Products

Declaration of the quantitative composition/potency labelling of biological medicinal products that contain modified proteins as active substance Description of composition of pegylated (conjugated) proteins in the summary of product characteristics Quality aspects included in the product information for vaccines for human use Potency labelling for insulin analogue containing products with particular reference to the use of "international units" or "units" Warning on transmissible agents in summary of product characteristics and package leaflets for plasma-derived medicinal products Points to consider for assessors - New factor VIII and factor IX products: potency determination for labelling and assays for testing post-infusion samples Potency declaration/labelling for biological medicinal products which contain modified proteins as active substance Adventitious agents safety evaluation Use of bovine serum in the manufacture of human biological medicinal products Use of porcine trypsin used in the manufacture of human biological medicinal products Virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses Testing for simian virus 40 (SV40) in polio virus vaccines Viral safety of oral poliovirus vaccine (OPV) Transmissible spongiform encephalopathies (TSEs) (animal and human) Investigation of manufacturing processes for plasma-derived medicinal products with regard to variant Creutzfeldt-Jakob disease risk Minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products Polysorbate 80 Re-establishment of working seeds and working cell banks using TSE compliant materials Investigational medicinal products Requirements for quality documentation concerning biological investigational medicinal products in clinical trials Virus safety evaluation of biotechnological investigational medicinal products Genetically modified organisms (GMOs) Environmental risk assessments for medicinal products containing, or consisting of, genetically modified organisms (GMOs) Scientific requirements for the environmental risk assessment of gene-therapy medicinal products

ATMPs: cosa sono?

Gene therapy medicinal products Cell-therapy and tissue engineering

Le norme riflettono sostanzialmente le GMP e le linee guidabiotech ma con peculiarità significative e tipiche di questiprodotti, come ad esempio:

- Manufacturing of small batch size (1 batch)- Personalized medicines- Difficoltà persino nella definizione della categoria di ATMP

La normative sugli ATMPs era un tempo integrata nella normative dei prodotti biotech: le loro peculiarità sono state via via sempre più riconosciute dalle autorità fino a meritarsi una normative (molto complessa) a sè stante.

ATMPs: particolarità della regolamentazione Forte caratterizzazione del vettore richiesta (incluse possibilità di integrazione), minimizzazione elementi addizionali Forte caratterizzazione di cellule/tessuti del donator Caratterizzazione banche cellulari e virali Controllo dei raw material (es. Tripsina) Dimostrazione dell’attività biologica Stabilità Follow up clinico

Questions and answers on comparability considerations for advanced therapy medicinal products

Reflection paper on design modifications of gene therapy medicinal products during development

Reflection paper on quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors

Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells

Guideline on non-clinical testing for inadvertent germline transmission of the gene transfer vectors

Reflection paper on management of clinical risks deriving from insertional mutagenesis Guideline on safety and efficacy follow-up and risk management of advanced therapy

medicinal products Guideline on potency testing of cell based immunotherapy medicinal products for the

treatment of cancer Reflection paper on stem cell-based medicinal products Reflection paper on clinical aspects related to tissue engineered products

Ph.Eur. monograph 5.14 Gene transfer medicinal products for human use

Ph.Eur. monograph on human haematopoietic stem cells (Cellulae stirpes haematopoieticae humanae) Version 7.2

Ph.Eur. monograph on Method of analysis (2.7.23.) Numeration of CD34/CD45+ cells in haematopoieticproducts. Version 7.2

Ph.Eur. monograph on Method of analysis (2.7.28.) Colony-forming cell assay for human haematopoieticprogenitor cells. Version 7.2

Ph.Eur. monograph on Flow Cytometry (2.7.24.) General chapter 5.2.12 Raw materials for the

production of cell-based and gene therapy medicinal products

VacciniI vaccini sono costituiti da molecole complesse e possono essere prodotti anche molto diversi tra loro (es. Antigeni, virus inattivati, vaccini ad acido nucleico).

Lotti molto grandi per far fronte alla domanda di mercato

Time costraint molto forti Garanzia di qualità ancora

maggiore rispetto ai prodotti biotech

I vaccini non sono una cura ma una protezione preventiva

Somministrati a persone SANE e primariamente alla popolazione più a rischio (anziani, bambini, persone

con patologie pre-esistenti ecc.)

Vaccini

Adjuvants in vaccines for human use Development of vaccinia virus-based vaccines against smallpox Influenza vaccines - quality module Quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines Requirements for vaccine antigen master file certification Scientific data requirements for a vaccine antigen master file Reduction, elimination or substitution of thiomersal in vaccines Evaluation of bovine spongiform encephalopathy risk via the use of materials of bovine origin in or during the manufacture of

vaccines Quality of water used in the production of vaccines for parenteral use Testing for simian virus 40 (SV40) in polio virus vaccines Viral safety of oral poliovirus vaccine (OPV) Stability and traceability requirements for vaccine intermediates Questions and answers on the Haemagglutination Inhibition (HI) test for qualification of influenza vaccine (inactivated) seed

preparations

In base al tipo di prodotto (antigene, virus inattivato, acido nucleico) si applicano le relative linee guida del mondo biotech nonchè linne guida specifiche per il mondo dei vaccini.

Emoderivati

Investigation of manufacturing processes for plasma-derived medicinal products with regard to variant Creutzfeldt-Jakobdisease risk

Plasma-derived medicinal products Replacement of rabbit pyrogen testing by an alternative test for

plasma derived medicinal products Viral safety of plasma-derived medicinal products with respect

to hepatitis E virus Requirements for plasma master file certification Epidemiological data on blood transmissible infections Validation of immunoassay for the detection of antibody to

human immunodeficiency virus in plasma pools Validation of immunoassay for the detection of hepatitis B

virus surface antigen in plasma pools Non-remunerated and remunerated donors: safety and supply

of plasma-derived medicinal products

Fattori di coagulazione Immunoglobuline Albumina Plasma

In generale si applicano le GMP e le linee guida dei prodotti biotech, in aggiunta a linee guida specifiche riguardanti topicmolto peculiari: Selezione donatori Controllo della contaminazione microbica e virale Processo di frazionamento/purificazione Viral clearance validation studies (including HIV, Epatite C-B, enveloped and non enveloped DNA viruses)

Agenda

Introduzione personale e dell’azienda PQE

Il processo di Drug Discovery ed il mondo biotech

Le linee guida applicabili all’ambito biotecnologico

Conclusioni

Conclusioni

Un farmaco chimico è estremamente diverso da un farmaco biologico.

Metodologie, processi, equipment, strumenti, strategie di controllo, studi di stabilità ecc. devono essere

gestite con una metodologia ed un mindset completamente diverso

È fondamentale appoggiarsi a persone tecnicamente competenti

SME azienda chimico farmaceutica background chimico

SME azienda biotech background biotecnologico/biologico

Molti aspetti dello sviluppo e della compliance di un farmaco biologico richiedono expertise ulteriormente

specializzate

La regolamentazione riflette la complessità del prodotto biotech e si inserisce

nel grande contesto generale delle buone norme di fabbricazione dei medicinali

Grazie a tutti!