Kvalitet biotehnoloških lekova: regulatorni aspekti · PDF fileBiotehnologija je... “bilo koja tehnološka primena u kojoj se koriste biološki sistemi, živi organizmi ili derivati

Agencija za lekove i medicinska sredstva Srbije

Kvalitet biotehnoloških lekova: regulatorni Kvalitet biotehnoloških lekova: regulatorni aspekti aspekti


www.alims.gov.rs 1

aspekti aspekti

Quality of biotechnology derived pharmaceutical products: regulatory aspects

Dr Milica Neši ć

Milica Neši ć, PhD

Biotehnologija je... Biotehnologija je... “bilo koja tehnološka primena u kojoj se koriste biološki sistemi, živi “bilo koja tehnološka primena u kojoj se koriste biološki sistemi, živi organizmi ili derivati da bi se stvorili ili modifikovali proizvodi ili procesi organizmi ili derivati da bi se stvorili ili modifikovali proizvodi ili procesi namenjeni specifičnoj upotrebi”namenjeni specifičnoj upotrebi”

Konvencija Ujedinjenih nacija o biološkom diverzitetu:Konvencija Ujedinjenih nacija o biološkom diverzitetu:

United Nations Convention on Biological Diversity:

..uz informacione tehnologije, najbrže rastuća industrija u 21. veku, koja samo u Evropi zapošljava oko ..uz informacione tehnologije, najbrže rastuća industrija u 21. veku, koja samo u Evropi zapošljava oko 22 miliona radnika.22 miliona radnika.

Biotechnology is...

“any technological application that uses biological systems, living organisms, or derivatives to make or modify products or processes for specific use.”...along with information technology, the biggest growth industry in the 21st century, and with 22 milion citizens ...along with information technology, the biggest growth industry in the 21st century, and with 22 milion citizens

employed in Europe alone.employed in Europe alone.

Biotehnologija je... Biotehnologija je... ...tehnologija sa vrlo različitim primenama:...tehnologija sa vrlo različitim primenama:

Biotechnology is...Biotechnology is......technology with a variety of applications:...technology with a variety of applications:

Zelena biotehnologija:Zelena biotehnologija: primene u agrikulturi i očuvanju životne sredineprimene u agrikulturi i očuvanju životne sredineGreen biotechnology:Green biotechnology: agricultural and enviromental applicationsagricultural and enviromental applications

Bela biotehnologija:Bela biotehnologija: primena u efikasnoj proizvodnji sirovinaprimena u efikasnoj proizvodnji sirovina

www.alims.gov.rswww.alims.gov.rs 3

Bela biotehnologija:Bela biotehnologija: primena u efikasnoj proizvodnji sirovinaprimena u efikasnoj proizvodnji sirovinaWhite biotechnology:White biotechnology: producing process feedstocks more efficientlyproducing process feedstocks more efficiently

Plava biotehnologija:Plava biotehnologija: primena biotehnologije kod morskih i vodenih organizamaprimena biotehnologije kod morskih i vodenih organizamaBlueBlue biotebiotecchnologhnologyy: : marine and aquatic applications of biotechnologymarine and aquatic applications of biotechnology

Crvena biotehnologija:Crvena biotehnologija: primena u medicini i farmacijiprimena u medicini i farmacijiRed biotechnology:Red biotechnology: medically and pharmaceutically relevant applicationsmedically and pharmaceutically relevant applications

Crvena biotehnologija / red biotechnologyCrvena biotehnologija / red biotechnology

Biotehnološki farmaceutski proizvod je bilo koji medicinski koristan lek čija proizvodnja uključuje žive organizme ili supstance koji živi organizmi proizvode.

Biotech pharmaceutical is simply any medically useful drug whose manufacture involves living organisms or substances that living organisms produce.


Prema ovako širokoj definiciji, u biotehnološke farmaceutske proizvode spadaju i vakcine, krvni derivati, prirodni alergeni, proizvodi namenjeni naprednim terapijama (genskoj i ćelijskoj terapiji) kao i proizvodi koji se smatraju biotehnološkim lekovima u užem smislu - proteini dobijeni tehnologijom rekombinantne DNK (monoklonska antitela, hormoni, enzimi, rekombinantni proteini drugih funcija).

According to this broad definition, biotech pharmaceutical products include vaccines, plasma derived products, allergens, advanced medicinal products (gene and cell therapy products), as well as products generally considered as biopharmaceuticals –recombinant DNA technology products (monoclonal antibodies, hormones, enzymes, recombinant proteins of other functions).

� Biotehnološki lekovi dobijeni tehnologijom rekombinantne DNKbiopharmaceuticals of rDNA origin

� Krvni derivati (proizvodi iz plazme)blood and plasma products

� Serumi i vakcinesera and vaccines

� Proteini iz prirodnih izvora (menotropin, protamin, goveñi i svinjski insulin...)proteins from natural sources (menothrophin, protamin, bovine and pig insulin)

biološki lekovi.*

biologicals


proteins from natural sources (menothrophin, protamin, bovine and pig insulin)

� Neki polisaharidi (heparin i heparini male molekulske mase)polysaccharides (heparin and LMW heparins)

� Neki mirkoorganizmi ili lizati mirkoorganizama (Lactobacillus, Streptococcus, Haemophillus...) some microorganisms and lysates of microorganisms

*Overview of Biological Active Substances of non-re combinant origin, CMDh, June 2007

biologicals

“Biološki lek je lek čiju aktivnu supstancu čini biološka supstanca proizvedena ili ekstrahovana iz biološkog izvora za čiju su kategorizaciju i kontrolu kvaliteta neophodna fizi čko-hemijsko-biološka ispitivanja, kao i opis proizv odnog procesa i njegova kontrola. “

Proizvodi namenjeni naprednim terapijama (genskoj i ćelijskoj terapiji) su kao vrlo specifični često izdvojeni u posebnu grupu.Advanced medicinal products (gene and cell therapy products) are very specific and usually thought of as

separated group of medicines.

Polisaharidni antibiotici, iako njihova proizvodnja uključuje žive organizme, su generalno izdvojeni u posebnu kategoriju i regulativom obuhvaćeni kao “proizvodi fermentacije”.Polysaccharide antibiotics, even though they are produced by living microorganisms, are separate category and regulated as “products of fermentation”


regulated as “products of fermentation”

Biljni lekovi su takoñe posebna kategorija.Herbal drugs are considered as separate class of medicines.

Zašto je to važno?Zašto je to važno?Why is that important?Why is that important?


Regulativa u oblasti kvaliteta lekova definiše veliki broj smernica, u početku pisanih za klasične (sintetske) farmaceutske proizvode;

Neke od smernica su primenljive i na biotehnološke proizvode, neke ne, a neke su specifične samo za njih. Treba izabrati pravi pristup.

Regulatory demands for quality of medicines are defined by a vast number of guidelines, firstly written in regard to usual (synthetic) pharmaceutical products;

Some of the guidelines are applicable to biotech products, some not, and some are biotech specific.Choosing the right approach is essential.

Zašto je to važno?Zašto je to važno?Why is that important?Why is that important?


Regulativa u oblasti kvaliteta lekova definiše veliki broj smernica, uglavnom napisanih za klasične (sintetske) farmaceutske proizvode;

Neke od smernica su primenljive i na biotehnološke proizvode, neke ne, a neke su specifične samo za njih. Treba izabrati pravi pristup.

Regulatory demands for quality of medicines are defined by a vast number of guidelines, mostly written in regard to usual (synthetic) pharmaceutical products;

Some of the guidelines are applicable to biotech products, some not, and some are biotech specific.Choosing the right approach is essential.

lekovi

medicines

biološki lekovi

biologicals

biotehnološki lekovi

biotechnological drugs


medicines biologicals biotechnological drugs

lekovi

medicines

biološki lekovi

biologicals

biotehnološki lekovi

biotechnological drugs

Najčešći biotehnološki lekovi:

Majority of biotechnological drugs:

1. hormoni hormones

2. citokini cytokines


medicines biologicals biotechnological drugs2. citokini cytokines

3. enzimi enzymes

4. faktori koagulacije clotting factors

5. vakcine vaccines

6. monoklonska antitela monoclonal antibodies(mogu biti proizvedena i tehnologijom hibridoma)(may also be produced by hybridoma technology)

7. ...


Biotehnološki lekovi do kraja 20.veka

Biotechnological products up to the end of 21st century


Biotehnološki lekovi do kraja 20.veka

Biotechnological products up to the end of 21st century

1973. stvoren je prvi rekombinantni organizam*In 1973. the first recombinant DNA organism was created

1975. 150 naučnika je preporučilo da Nacionalni institut za zaštitu zdravlja da smernice za istraživanja rekombinantne DNK (Asilomar konferencija)In 1975. 150 scientes have recomended that the National Institute of Health provide guidelines for recombinant DNA research (Asilomar conference)

Nepunu deceniju kasnije...Less than a decade later...

28.10.1982. Humulin-rekombinantni humani insulin recombinant human insulin

-proizveden u ćelijama E.coli K12 produced in E.coli K12


-u toku registracije tretiran kao nova aktivna supstanca, iako se njegova aminokiselinska struktura prirodno javlja u ljudskom organizmu during approval treated as new molecular entity (NME), even though its amino acid sequence occurs naturaly in humans

*Herb Boyer (UCSF), Stanley Cohen (Stanford University). An antibiotic resistance gene introduced into E.coli bacteria

Regulatorni izazoviRegulatorni izazoviRegulatory chalengesRegulatory chalenges

Imune reakcije pacijenata?

Immune reactions in patients?

Proteini ćelije domaćina? DNK ćelije domaćina?

Host cell proteins? Host cell DNA?

Koji su GMP zahtevi?

What are the GMP requirements?

Kako kontrolisati kvalitet ovakvih lekova?

How to control the quality of such drugs?


Da li će rekombinantna E.coli biti opasnost za okolinu?

Is recombinant E.coli an enviromental risk?

Da li se mogu uspešno ukloniti kontaminanti procesa fermentacije?

Can fermentation proces contaminants be succecfully removed?

Virusi?

Viruses?

Kako obezbediti ujednačen proizvodni proces?

How to ensure uniform production process?

Kako upravljati izmenama?

How to manage changes?

Evropska regulativaEuropean legislative:

-Zakoni regulations

-Direktive directives

-Guidelines smernice

Ph.Eur.

Zakon EU je iznad nacionalnih zakona

Law superordinated to any national law

Direktive imaju težinu zakona i implementiraju se u nacionalnim zakonima

Law, to be implemented ina national law

Smernice nisu zakon, ali sadrže najsavremenije

informacije

No law. State of the Art

information


Krenuti od krova ili od temelja?Krenuti od krova ili od temelja?Start from the roof or from the foundation?Start from the roof or from the foundation?

USP/FDA

Meñunarodno harmonizovana regulativa (ICH)Internationaly harmonised regulations (ICH)

information


DirektiveDirectives

EMA: smerniceEMA guidelines

naučni komitet za medicinske proizvode za humanu upotrebu (CHMP), grupa za biološke lekove


naučni komitet za medicinske proizvode za humanu upotrebu (CHMP), grupa za biološke lekove (BWP)

ICH: smerniceICH guidelines

EDQM: Ph.Eur.

Direktive Direktive DirectivesDirectives

Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member Statesrelating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products

DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of6 November 2001 on the Community code relating to m edicinal products for human use



DirektiveDirectives






EDQM: Ph.Eur.

EMA: smerniceEMA: smerniceEMA guidelinesEMA guidelines

3AB1a Production and Quality Control of Medicinal Product s derived by recombinant DNATechnology (First adopted June 1987; This version adopted December 1994; Date of entry into forceJuly 1995)

3AB3a Production and Quality Control of Cytokine Products derived by Biotechnological Processes(Date of first adoption February 1990; Date of entry into force August 1990)

3AB5a Quality of Biotechnological Products: Stability Test ing of Biotechnological/BiologicalProducts *) (Date of first adoption December 1995; Date of entry into force July 1996) - ICH Q5C, CPMP/ICH/138/95

CPMP/ICH/139/95 Quality of Biotechnological Products: Analysis of t he Expression Construct in CellLines Used for Production of r-DNA Derived Protein Products July 1996 - ICH Q5B

CPMP/ICH/295/95 Quality Of Biotechnological Products: Viral Safety Evaluation Of Biotechnology Products Derived From Cell Lines Of Human Or Animal Origin October 1997 - ICH Q5A (R1)


CPMP/ICH/295/95 Quality Of Biotechnological Products: Viral Safety Evaluation Of Biotechnology Products Derived From Cell Lines Of Human Or Animal Origin October 1997 - ICH Q5A (R1)

CPMP/ICH/294/95 Quality of Biotechnological Products: Derivation an d Characterization of CellSubstrates Used for Production of Biotechnological /B iological Products March 1998 - ICH Q5D

CPMP/ICH/365/96 Specifications: Test Procedures and Acceptance Crit eria forBiotechnological/Biological Products September 1999 - ICH Q6B

CPMP/ICH/5721/03 Biotechnological/Biological Products Subject To Chan ges In Their Manufacturing Process December 2004 - ICH Q5E

EMEA/CHMP/BWP/157653/2007 Guideline On Development, Production, Characterizat ion AndSpecifications For Monoclonal Antibodies And Relate d Products December 2008

EMA/CHMP/ICH/425213/2011 ICH guideline Q11 on development and manufacture of dru g substances (chemical entities and biotechnological/ biological entities) May 2011

Biological guidelines: http://www.ema.europa.eu/ema/index.jsp?curl=pages/r egulation/general/general_content_000082.jsp&mid=WC 0b01ac0580027547

EMA: smerniceEMA: smerniceEMA guidelinesEMA guidelines

EMA/CHMP/BWP/25360/2011Concept paper on the need for a guideline on proces s validation of medicinal products containing biotechnology derived proteins as active substanceMay 2011.


EMA/CHMP/BWP/187338/2014 Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission (Draft)



DirektiveDirectives






EDQM: Ph.Eur.

www.alims.gov.rswww.alims.gov.rs 23http://www.ich.org/products/guidelines/quality/arti cle/quality-guidelines.html

ICH smernice za kvalitet biotehnoloških lekovaICH smernice za kvalitet biotehnoloških lekova

ICH guidelines for quality of biotechnological productsICH guidelines for quality of biotechnological products


U proceni kvaliteta biotehnoloških lekova primenjuju se i druge smernice koje nisu specifične za biotehnološke lekove, a u kojima je navedeno da se odnose i na biotehnološke lekove (npr. Q3D, Q11) ili u kojima nije navedeno da se na njih ne odnose (npr. Q3C).

Evaluation of quality of biotechnological products should also implement other guidelines that state their applicability to biotechs (e.g. Q3D, Q11), or do not state their inapplicability (e.g. Q3C).

UVEK PROVERITI “SCOPE”! ALWAYS CHECK “SCOPE”!


DirektiveDirectives






EDQM: Ph.Eur.

Ph.Eur.Ph.Eur.verzija 8.2, od 01.07.2014.verzija 8.2, od 01.07.2014.

-oko 270 opštih testova/metodaapprox. 270 general methods

-oko 1800 monografija za aktivne supstance (specifičnih i opštih)approx. 1800 specific and general substance monographs

-od toga za biotehnološke lekove manje od 30for biotech products less than 30


Opšte monografije general monographs

0784 Products of recombinant DNA technology

2013 Monoclonal antibodies for human use

2034 Substances for pharmaceutical use

1483 Products with risk of transmitting agents of animal spongioform encephalopathies


Posebne monografije specific monographs

07/2011:1056 Hepatitis B vaccine rDNA (i kombinovane vakcine koje sadrže ovu komponentu 2062, 1933, 1526)

07/2011:2441 Human papillomavirus vaccine rDNA07/2013:1170, corrected 8.0 Alteplase for injection01/2008:0471 Calcitonin (salmon)01/2008:1316 Erythropoietin concentrated solution


01/2008:1316 Erythropoietin concentrated solution07/2010:2206 corrected 7.6 Filgrastim concentrated solution01/2014:2285 corrected 8.1 Follitropin01/2014:2286 corrected 8.1 Follitropin concentrated solution07/2013:1635 Glucagon, human07/2014:2522 Human coagulation factor IX rDNA concentrated solution01/2008:1643 Human coagulation factor VIII (rDNA)01/2014:2534 Human coagulation factor VIIa (rDNA) concentrated solution


Posebne monografije specific monographs

01/2008:2084 corrected 6.0 Insulin aspart01/2014:2571 Insulin glargine01/2011:0838 Insulin, human (proizveden modifikacijom svinjskog insulina ili tehnologijom

rekombinantne DNK)01/2008:2085 corrected 6.0 Insulin lispro01/2008:1110 Interferon alfa-2 concentrated solution


01/2008:1110 Interferon alfa-2 concentrated solution01/2009:1639 corrected 7.6 Interferon beta-1a concentrated solution07/2014:1440 Interferon gamma-1b concentrated solution01/2008:1641 Molgramostim concentrated solution01/2008:0951 corrected 7.0/ Somatropin01/2008:0950 corrected 7.0 Somatropin concentrated solution01/2008:0952 corrected 7.0 Somatropin for injection

hormoni hormones

citokini cytokines

enzimi enzymesIma nekih posebnih monografija u Ph.Eur.

There are some specific monographs in Ph.Eur.


faktori koagulacije clotting factors

vakcine vaccines

monoklonska antitela monoclonal antibodies

There are some specific monographs in Ph.Eur.

2013 Monoclonal antibodies for human use

Registrovana monoklonska antitela u Srbiji:Registrovana monoklonska antitela u Srbiji:Licensed monoclonal antibodies in SerbiaLicensed monoclonal antibodies in Serbia

belimumabcertolizumabtrastuzumab

obinutuzumabtocilizumab

bevacizumabcetuksimab

certolizumabadalimumab


adalimumabranibizumab

rituksimabdenosumabinfliksimabgolimumab

baziliksimabustekinumab

pavlizumabnatalizumab

panitumumabomalizumabbelimumab


Håkan Mellstedt, Clinical considerations for biosimilar antibodies; EJC Supplements, Volume 11, Issue 3 , Pages 1–11, December 2013

Kvalitet zavisi od... svega!Kvalitet zavisi od... svega!The quality is directed by... everythingThe quality is directed by... everything

Domaćin?Host?

Konstrukt?Construct?

Ubiranje proizvoda?Harvest?

Posttranslacione modifikacije?Posttranslational modifications?


Praćenje raznovrsnih pravaca razvoja industrije predstavlja izazov za regulatorne organeRegulators are chalenged to keep up with versatile routes of industrial development.

Za nove biotehnološke proizvode proizvoñači često kroz diskusiju sa regulatornim telom (EMA, FDA) pre predavanja zahteva definišu pristup za specifične i nove izazove.

For new biotech products approach for specific new chalanges is often discussed with regulators (FDA, EMA)

Prečišćavanje?Purification?

EPO structure, Chemical & Engineering News, ISSN 000 9-2347, Copyright © 2010 American Chemical SocietyJ une 5, 2006, Volume 84, Number 23, pp. 64-65

Karakterizacija?Characterisation?

Razvoj biotehnologije: unapreñenje procesa Razvoj biotehnologije: unapreñenje procesa proizvodnje za lekove koji su već na tržištuproizvodnje za lekove koji su već na tržištu

Biotechnology development: improvement of production process of registered drugsBiotechnology development: improvement of production process of registered drugs

Unapreñenja procesa su česta (i poželjna) - serum free medijum, scale-up, razvoj savremenih analitičkih metoda što omogućava bolju karakterizaciju aktivne supstance...Process improvements are numerous (and desirable) - serum free medium, scale-up,


Process improvements are numerous (and desirable) - serum free medium, scale-up, development of state-of-the-art analytical methods enabling better characterization of active substance...

Za biotehnološke lekove se prijavljuje veliki broj varijacijaFor biopharmaceuticals usually a great number of variations is proposed

Procena izmena je kompleksna (npr. samo scale-up proizvodnog procesa može dovesti do izmenjenog profila glikozilacije)Evaluation of changes is very complex (e.g. process scale-up can lead to changes in glycosilation profile)

Razvoj biotehnologije: novi lekoviRazvoj biotehnologije: novi lekoviBiotechnology development: new drugsBiotechnology development: new drugs

� Proizvodnja proteina tehnologijom rekombinantne DNK je postala “rutina”, a sekvenciranje humanog genoma i razvoj bioinformatičkih alata omogućava veliki broj “ciljeva”Production of proteins by recombinant DNA technology has become a routine, with sequencing of the human genome and development of bioinformatical tools providing for numerous targets

� Razmatra se veliki broj novih aktivnih supstanciA large number of new active substances is under evaluation

� 1/1000 stigne do kliničkih ispitivanja1/1000 makes it to the clinical trials


� 1/5 stigne do tržišta1/5 makes it to the market

� 1/3 na tržištu isplati ulaganja1/3 on market bring in enough revenues to recover their costs

� Ipak, oko 10 % tržišta zauzimaju biotehnološki lekovi, i njihov broj raste brže nego broj sintetskih lekovaNevertheless, biotech drugs, represent an estimated 10% of the total global prescription drugs marketon market, with their number increasing faster then the number of sinthetic drugs.

� U razvoju je i veliki broj novih tehnologija (pored ćelija bakterija, kvasaca, animalnih i humanih modela razvijaju se i platforme na ćelijama insekata i biljaka (Physcomitrella - mahovina, biljne ćelije -FOTO-BIOREAKTOR)New technologies are under expansion (in addition to bacterial, yeast, animal and human cells models, platforms based on insect and plant cells are developing)


� Proizvodnja proteina tehnologijom rekombinantne DNK je postala “rutina”...Production of proteins by recombinant DNA technology has become a routine...

� Za sve veći broj registrovanih biotehnoloških lekova ističe patentna zaštitaFor increasing number of registered biotechnological drugs patent protection is expiring

� Zemlje kao što su Indija, Kina i Brazil ulažu znatna sredstva u razvoj farmaceutske industrije (i biotehnoloških lekova). Rusija u programima nabavke lekova za odreñene grupe pacijenata daje prednost domaćim lekovima koji moraju činiti najmanje 30%

Razvoj biotehnologije: biološki slični lekoviRazvoj biotehnologije: biološki slični lekoviBiotechnology development: biosimilarsBiotechnology development: biosimilars


grupe pacijenata daje prednost domaćim lekovima koji moraju činiti najmanje 30% nabavljene količine što stimuliše razvoj biotehnoloških kompanijaCountries such as India, China and Brazil are investing substantial funds in development of pharmaceutical industry (biotech included). Russia has federal programs to supply drugs for certain groups of patients which giveofficial preference to domestically manufactured medicines that must constitute at least 30% of supply, thus stimulating domestic biotech producers

� Očekuje nas veliki broj zahteva za registraciju biološk i sli čnih lekova, gde će jedan od najve ćih izazova biti proceniti uporedivost proizvoda sa stanovišta kvaliteta...We should expect a great number of applications for biosimilars, with quality comparison of products a s one of mayor challenges in evaluation process...


Hvala na pažnjiHvala na pažnji

Thank you for your attention


www.alims.gov.rs 37

Thank you for your attention

Dr Milica Neši ćProcena dokumentacije o kvalitetu leka


Vojvode Stepe 458, 11 000 Beograd, Srbija

+381 11 3951 154

[email protected]

Milica Neši ć, PhDEvaluation of quality documentation

Medicines and Medical devices Agency of Serbia

458 Vojvode Stepe street, 11 000 Belgrade, Serbia

+381 11 3951 154

[email protected]

Agencija za lekove i medicinska sredstva SrbijeBeograd, Vojvode Stepe 458

[email protected]

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Kvalitet biotehnoloških lekova: regulatorni aspekti · PDF fileBiotehnologija je... “bilo koja tehnološka primena u kojoj se koriste biološki sistemi, živi organizmi ili derivati