Dr V Symposium SINDUSFARMA - ISP/FIP - ANVISA New...

Dr R. Balocco, Group Lead, INN Programme

V Symposium SINDUSFARMA - ISP/FIP - ANVISA

New frontiers in manufacturing technology, regulatory sceince and pharmaceutical quality system

Brasilia, 22-23 June 2016

Naming of Biological products:

Perspectives and WHO proposals





What's in a name?

Safety

Quality

Information

Regulation Rational use use

Procurement

Efficacy





Verba volant scripta manent

"By assigning a single international name to drugs,

WHO helps ensure that a prescription filled

abroad is what doctor ordered back home."

Dr Margaret Chan, Director General





The WHO International Nonproprietary

Name (INN) Programme

To provide one single name worldwide for active

pharmaceutical substances

Initiated in 1950 by resolution WHA3.11

Operational since 1953

Based on WHO Constitution





INN Programme

Mandated by the Member States in 1953

One of the oldest WHO programmes

To devise a single name for a substance

INNs are recognized in almost all Member States

INNs can be used freely and cannot be registered as

trade names

Not concerned with formulations





Interested parties outside WHO

USAN Program

Pharmacopoeias

(BP, FP, USP, JP….)

European Commission,

WCO, WIPO, …

Applicants:

Research based

industry,

nomenclature bodies

National trade-mark

authorities

DRAs

(EMA, US-FDA….)

INN Programme





INNs…

Unique name

Distinctive in sound and spelling

Not liable to confusion with other names in common

use

Formally placed by WHO in the public domain

Can be used without any restriction to identify

pharmaceutical substances





Reaching the world

INNs Lists are published in WHO Drug Information

All INNs are published in a Cumulative List

On-line INN information: Mednet - INN Extranet

Global Data Hub

http://mednet.who.int/









MedNet

communities.net/inn/-https://mednet

https://mednet-communities.net/inn/







Medicines on the market New medicines in development

(European Commission 2005)

An expanding area within pharmacy





Old and current challenges

The complexity

The number-induced difficulty

The emerging of new types of substances

Aspirin

monoclonal antibody

Kozlowski et al. 2011





To apply INN for biologicals

ADDITIONAL INFORMATION TO BE PROVIDED :

Complete mature amino acid sequence (in a format that can be copied for analysis )

Positions of disulfide bridges and post-translational modifications

Glycosylation pattern (site, type of sugar, etc.)

Expression system (type of cells) and clone names

Comparison with native sequence

Precursor nucleotide sequence (for antibodies and nucleotide-based substances)

Details of pegylation and linker

(…)

CHECK FOR UPDATED LIST IN THE INN APPLICATION FORM





General policies

• Blood products natural excluded

• Fusion proteins

• Gene therapy products

• Glycosylated proteins/peptides

• Non-glycosylated proteins/peptides

• Immunoglobulins excluded

• Monoclonal antibodies

• Skin substitutes excluded

• Transgenic products

• Vaccines most excluded

• Cell therapy products

http://www.who.int/medicines/services/inn/BioRev2014.pdf?ua=1.





Glycosylated proteins/peptides

• Identify the group with a stem (ex. -poetin)

• Indicate differences in the amino acid sequence with a random prefix (ex. darbepoetin)

• Indicate differences in the glycosylation pattern with a Greek letter in full as second word (ex. darbepoetin alfa)

Greek letters assigned in the alphabetical sequence as applications received !





Existing INN stems

Stem Name of the group Stem Name of the group

-relix Gonadotropin-releasing-hormone (GnRH) inhibitors, peptides

-rsen antisense oligonucleotides

-kinra interleukin receptor antagonists -cogin blood coagulation cascade inhibitors

-kin interleukin type substances -cog blood coagulation factors

-mab monoclonal antibodies -stim colony stimulating factors

-tocin oxytocin derivatives -ase enzymes

-tide peptides and glycopeptides (for special groups of peptides see -actide, -pressin, -relin, -tocin)

-poetin erythropoietin type blood factors

-relin pituitary hormone-release stimulating peptides -ermin growth factors

-cept receptor molecules, native or modified (a preceding infix should designate the target)

som- growth hormone derivatives

-actide synthetic polypeptides with a corticotropin-like action

-parin heparin derivatives including low molecular mass heparins

-pressin vasoconstrictors, vasopressin derivatives -irudin hirudin derivatives





Biological groups with INN Schemes

Monoclonal antibodies (mAbs)

Gene therapy products (GTPs)

Cell therapy products (CTPs)

…





Naming scheme for mAbs

Prefix (random) + substem A + substem B + stem (-mab)

Ex. drozitumab (103)(65) ; olokizumab (103)(65)

substem A Target Class

-ami- serum amyloid protein

(SAP)/amyloidosis (pre-substem)

-b(a)- bacterial

-c(i)- cardiovascular

-f(u)- fungal

-gr(o)- skeletal muscle mass related growth

factors and receptors (pre-substem)

-k(i)- interleukin

-l(i)- immunomodulating

-n(e)- neural

-t(u)- tumour

-v(i)- viral

substem B Species

a rat

axo rat-mouse (pre-sub-stem)

e hamster

i primate

o mouse

u human

-vet- veterinary use (pre-sub-stem)

xi chimeric

-xizu- chimeric-human(ized)

zu humanized





Gene therapy products: two-word names

Word 1: gene component

Prefix Infix Suffix

random To identify the gene :

-ermin- growth factor; -kin- interleukin; -lim- immunomodulator…

-(a vowel)gene

Word 2: vector component

Ex: golnerminogene pradenovec (101)(63); velimogene aliplasmid (97)(59)

Prefix Infix Suffix

random To indicate the type of viral vector:

-lenti- lentivirus; -adeno- adenovirus ; -herpa- herpes v.

-vec non-replicating v.

-repvec replicating v.

-plasmid plasmid





INN-USAN-harmonized nomenclature

scheme cell therapy products

Prefix Infix 1: Manipulation / s

Infix 2: Cell type

Suffix : -cel

random By using existing infixes for manipulation :

e.g.

-gen-: transduced (genetic modification)

-fus- : fusion to a cell

By using existing infixes for cell types :

e.g.

-den- dendritic cells

-co(n)- chondrocytes

-mio(b)- myoblasts

-tu- tumor cells

-tem- stem cells

...

to name all CTP

Exception:

-Minimally manipulated

hematopoietic elements,

-combination products

Ex: old scheme: tragenpumeltulocel new scheme: tragentucel





INN for mAbs

INN for mAbs were introduced in 1991 (pINN List 66)

The process for them needs to accommodate the large

number of potential mAb products

It also needs to provide some information on target,

sequence, production method and immunology

The process needs to be periodically assessed and, if

needed, modified to take account of

scientific/technical advances





How to name mAbs in INN

INN for monoclonal antibodies (mAbs) are composed

of a prefix, a substem A, a substem B and a suffix

The common stem for mAbs is -mab, placed as a

suffix

The stem -mab is to be used for all products

containing an immunoglobulin variable domain which

binds to a defined target

International Nonproprietary Names (INN) for biological and biotechnological substances (a review) Bioreview 2014





How to name mAbs in INN

Substem B indicates the species on which the

immunoglobulin sequence of the mAb is based:

ex: -o- mouse, -u- human, -xi- chimeric,

-zu- humanized…

Substem A indicates the target (molecule, cell, organ)

class:

ex: -c(i)- cardiovascular, -k(i)- interleukin,

-t(u)- tumour…

International Nonproprietary Names (INN) for biological and biotechnological substances (a review) Bioreview 2014





Summary and conclusion

How to name biological and biotechnological

substances:

General Policies

Stems

Schemes

All information and updates at:

http://www.who.int/medicines/services/inn/inn_bio/en/





INN a global name?

epoetin alfa (2x)

epoetin zeta epoetin kappa

(generic recombination)

epoetin alfa biosimilar 1

epoetin lambda





……

This is an issue that does need to be addressed globally,

and soon

The WHO INN Programme has a clear mandate

The need for a harmonized (global) system is crucial





History of the Biological Qualifier (BQ)

Some NRA’s requested a global means of identification

of biosimilars

The BQ Proposal developed in consultation with experts

and NRAs and published in Jul 2014

Extensive feedback from all sectors guiding modification

of the Proposal

Feedback to and from NRAs (Mar 2015) & stakeholders

(Jun 2015)





Response from whom?

Academic

Government

Manufact'rs

Industry

Clinical org

Comms org

Funding org

Patient org

Pharm'st org

Personal





Support?

1 - strongly disagree

2 - disagree

3 - partially agree

4 - agree

5 - strongly agree





Whose support?

0

5

10

15

20

25

Negative (1-2)

Neutral (3)

Positive (4-5)





Government support?

0

1

2

3

4

5

6

7

8

9

Asia Canada EMA Europe LatinAmerica

USA

Negative

Neutral

Positive





Summary of current Proposal

BQ for ALL biological medicines to identify drug

substances made by 1 process under 1 quality system

BQ assigned to a BQ Applicant who permits MAHs to use

it for products containing the drug substance

Used to minimise mis-prescription and/or dispensing,

pharmacovigilance & global transfer of prescriptions

BQ is assigned by an automated online system





Summary of current Proposal

If the amino acid sequence is unchanged the INN &

BQ remain the same for the life of the drug

substance

If a change is made in which glycosylation is not

comparable, then a new Greek letter and BQ.

INN informed by BQ Applicant and/or NRA of such a

change





Format and future

The Proposal had become cumbersome through the

incorporation of feedback and lengthy explanations

of decisions

Separated into concise Proposal and a lengthy

Frequently Asked Questions (FAQ) document

Presented to INN Experts on Fri 17 Oct 2015 and

ongoing consultation with NRAs and other

stakeholders. A way forward agreed in April 2016.





Conclusion

Majority of stakeholders support BQ, but there is

some opposition.

BQ Proposal modified in response to objections &

suggestions receiving further positive and negative

feedback.

INN will continue to develop &, at the appropriate

time, enhance the concept.





http://blog.gembaacademy.com/wp-content/uploads/2009/04/simplicity.jpg





INN is simple

"Simplicity is the ultimate sophistication"

Leonardo Da Vinci





Obrigado

Thank you! Grazie! Danke! Merci!

Obrigado ! Gracias 谢谢！ありがう！ARIGATOU！ Dziękuję! Dank je / u!

Mulţumesc! Teşekkür ederim! Tack!Tack så

mycket! Kiitos! תודה לך! Takk! ďakujem,

ďakujem vám ;

Hvala! ً شكرا!shokran Ευχαριστώ! 감사합니다 Děkuji! Tak skal du have! Dankon! Hvala,

Hvala lepa, Najlepša hvala Gràcies!

Faleminderit Hvala! Ačiū, De’koju, Labai ačiū

ขอบคณุ ; ขอบคณุมาก(khàwp khun) ; (khàwp khun

mâak) shukrīya (شكريهً) بہت(bahut( Cảm ơn cô ;

Cảm ơn cô nhiều; Благодаря!Благодаря! Obrigado!” Gracias Þakka þér! baie dankie

; Takk fyri! Sipas

dekem متشکرم! Благодарам! Hvala Vam! V

Təşəkkür Paldies!Pateicos! / Tencinu! Terima

kasih Дуже дякую ;Дякую ; Спасибі! Баярлалаа ; Гялайлаа ; Танд их

баярлалаа Terima kasih ধন্যবাদ

(dhonyobād( Salamat! Trugarez ! Mersi

!Trugarez Danke!

Thank you! Grazie! Danke! Merci! Obrigado ! Gracias 谢谢！ありがう！ARIGATOU！ Dziękuję! Dank je / u!

Mulţumesc! Teşekkür ederim! Tack!Tack så mycket! Kiitos!

; Takk! ďakujem, ďakujem vám !תודה לך

Hvala! ً شكرا!shokran Ευχαριστώ! 감사합니다 Děkuji! Tak

skal du have! Dankon! Hvala, Hvala lepa, Najlepša hvala

Gràcies! Faleminderit Hvala! Ačiū, De’koju, Labai ačiū ขอบคณุ ; ขอบคณุมาก(khàwp khun) ; (khàwp khun mâak) shukrīya (بہت (

;bahut( Cảm ơn cô ; Cảm ơn cô nhiều)شكريهً

Благодаря!Благодаря! Obrigado!” Gracias Þakka þér! baie

dankie ; Takk fyri! Sipas

dekem متشکرم! Благодарам! Hvala Vam! V

Təşəkkür Paldies!Pateicos! / Tencinu! Terima kasih Дуже дякую ;Дякую ; Спасибі! Баярлалаа ; Гялайлаа ; Танд

их баярлалаа Terima kasih ধন্যবাদ

(dhonyobād( Salamat! Trugarez ! Mersi !Trugarez Danke!

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