351al - BCM6013 - BPF - 2011.ppt)esilrch1.esi.umontreal.ca/~syguschj/cours/BCM6013/2011/expression... · not enough: the whole organisation has to be compliant to GMP. • Not just

BCM6013 Good Manufacturing Practices May 6, 2011

FvL Frank van Lier 1 of 20

1

FvL Frank van Lier Consultancy

Course BCM6013Course BCM6013

Good Manufacturing Practices

4

• Introduction• Presenter

• Presentation

• Pharmaceutical industry• Products

• Timeline

• Scale

• GMP in practice• Documentation

• Manufacturing

• Technology transfer

• Building

• Equipement

• Materials

• Personnel

• Quality Control

• Validation

• Change control

TopicsTopics

5

Product Life CycleProduct Life Cycle



6

GMP: patient protectionGMP: patient protection

Product

Directly inserted:

bypass of several

defence barriers

Patient has already lowered

defences due to illness

PatientManufacturing

7

Good Manufacturing PracticesGood Manufacturing Practices

• To ensure the quality of pharmaceutical products and thus protecting patients.

• GMP applies to the building and equipment, but this is not enough: the whole organisation has to be compliant to GMP.

• Not just practices: they are mandatory - by law - and required for production of material administered to patients.

8

RegulationsRegulations

…………..Autres

European MedicineAgency (EMA)

Eudralex vol. 4Europe

Food and DrugsAdministration (FDA)

Code of Federal RegulationsCFR 21

United States

Health CanadaTitle 2 Food and DrrugRegulations

Canada

Controlled byRegulationRegion



9

WhatWhat isis GMP ?GMP ?

Regulations that define the minimum practices for

methods, facilities and controls used for

the manufacture, processing, packing, or holding of a drug to

assure that such a drug meets the requirements of the act as to

safety, and has the

identity and

strength and meets the the

quality and

purity characteristics that it purports or is represented to possess.

10

ProductsProducts basedbased on on cellcell cultureculture

• Vaccines

• Secondary metabolites (penicillin)

• Polypeptides (insulin) and proteins (monoclonal antibodies)

• Cellular therapy

11

Sales Sales biotechbiotech 2009 (billion $)2009 (billion $)

0

2

4

6

Enbrel

Remicade

Avastin

Humira

Rituximab

Lovenox

Lantus

Herceptin

Neulasta

Epogen

Amgen

Roche

Others

HormoneAntibody

E. coli

Heparin G-CSF / IL-2



12

Scale up

FromFrom ideaidea to final to final productproduct

Process development

(Clinical) Tests

13

Cost

Quality

Timeline

Project driversProject drivers

15

TypicalTypical BioBio--pharmapharma processprocess

Geneticallymodified cell

Formulation

Primaryrecovery

Purification

Culture / fermentation

Filling andpackaging



16

• Bacterium

• Yeast

• Fungus

• Insect cell

• Mammalian cell

• Human cell

OrganismesOrganismes

17

FDA FDA approvalsapprovals

0

2

4

6

8

1982 1985 1988 1991 1994 1997 2000 2003 2006

Mammaliancells: 55

E. Coli: 38

S. cerevisiae: 11

18

Fermentation / Fermentation / primaryprimary recoveryrecovery

P

Bacterium

Cell

Vial Flasks Bioreactors

Separation

Intra-ce

llular

Extra-

cellu

lar

Extra-cellular

Inclusion bodies

Cell rupture

Solubilisation and refolding



19

FlaskFlask andand bioreactorbioreactor

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PurificationPurification

Concentration Capture step Inactivation virus Flow-through step

Concentration Polish step Concentration

API

21

PurificationPurification

Buffer vessel

Column

Control system



22

DosingDosing

• Oral

• Rectal

• Ophtalmic

• Otic

• Parenteral

• Topic

• Vaginal

23

Formulation, Formulation, fillingfilling

Stabiliser

others

API

Drug

Drug

Drug Drug Drug Drug Drug Drug

Filling

Product

Lyophilisation

Formulation

24

Scale up:Scale up: by numberby number



25

DSM Capua, Italy

Scale upScale up: by: by volumevolume

26

QuestionQuestion

• Reactor scale EPO?• (A) <10 L

• (B) 10 - 100 L

• (C) 100 - 1 000 L

• (D) 1 000 -10 000 L

• (E) > 10 000 L

Erythropoetin (EPO): first blockbuster productproduced with animal cells

28

EffectEffect timetime lineline

Development Monopoly Competition

Price

Patent protection



30

Time lineTime line

0 5 10 15

Research

Development

Pre-clinical testing

Clinicaltrials

Phase I

Phase III

Phase II

Approval

Launch

GMP

32

GoodGood ManufacturingManufacturing PracticesPractices

• Quality Standards

• Complaints

• Returns

• Change control

• Validation

• Manufacturing

• Quality Control

• Stability studies

• Training

• Deviations

• Technology Transfer

• Equipement and building

• Audit Management

• Development

• Supplier qualification

• Lot disposition

• Annual product review

• Documentation

• Storage and distribution

• Quality Assurance

33

DocumentationDocumentation

GreatMass ofPaper



34

Documentation Documentation principleprinciple

How to do it:

Standard OperatingProcedures

Protocols

What was done:

Batch Records

Logbooks

Reports

Do what is written;

Write what was done

35

Main Main elementselements

building

equipment

materials

personnel

P -1 / V -1 0 1

M i x i n g

P -2 / S T -1 0 1

He a t S te ri l i z a ti o n

P -4 / G-1 0 1

Ce n tri fu g a l Co m p re s s i o n

P -5 / A F -1 0 1

Ai r F i l tra ti o n

P -6 / A F -1 0 2

Ai r F i l tra ti o n

P -7 / V -1 0 2

F e rm e n ta ti o n

P -9 / D S -1 0 1

Ce n tri fu g a ti o n

P -1 1 / H G-1 0 1

Ho m o g e n i z a ti o n

P -1 3 / D S -1 0 1

Ce n tri fu g a ti o n

P -1 4 / D S -1 0 1

Ce n tri fu g a ti o nP -1 6 / D F -1 0 1

Di a fi l tra ti o nP -1 7 / D E -1 0 1

De a d -E n d F i l tra ti o n

M e d i a S -1 0 2

S -1 0 5 S -1 0 6

S -1 0 7

S -1 0 8

A i r

S -1 1 0

A m m o n i aS -1 1 2

S -1 1 3

S -1 3 0

S -1 2 0

S -1 3 1

S -1 3 3

W F I -1

S -1 3 2

L i q W a s t e 4

L i q W a s t e 5

W a t e r

P -1 9 / V -1 0 6

S to ra g e

S -1 0 1

S -1 0 3

S -1 0 4

P -8 / V -1 0 3

I B S o l u b i l i z a ti o n

S -1 0 9

S -1 1 5

P -1 5 / V -1 0 3

CNBr Cl e a v a g e

S -1 1 1

S -1 2 1

CNBr/ HCOOH

M rE T OH/ Ure a

L i q w a s t e 1

L i q W a s t e 2

S -1 1 4

L i q W a s t e 3

P -1 8 / C S P -1 0 1

Ro ta ry E v a p o ra to r

S -1 1 7

P -2 0 / V -1 0 5

S u l fi to l y s i s

S -1 2 2

Gu a n HCl

P -2 1 / D F -1 0 1

Di a fi l tra ti o n

W F I -2

L i q W a s t e 6

P -2 3 / V -1 0 7

Re fo l d i n g

P -2 4 / D F -1 0 2


P -2 6 / V -1 0 8

E n z y m e Co n v e rs i o n

P -2 7 / D F -1 0 2


P -2 9 / D F -1 0 3


P -3 1 / C -1 0 5

Ge l F i l tra ti o n

P -3 4 / B C F -1 0 1

Ba s k e t Ce n tri fu g a ti o n

P -3 5 / F D R -1 0 1

F re e z e Dry i n g

S -1 2 7

S -1 2 8

S -1 2 9

P -3 6 / C -1 0 1

S -S e p h a ro s e

P -2 2 / C -1 0 2

HI C Co l u m n

P -2 5 / C -1 0 3

S -S e p h a ro s e

P -2 8 / C -1 0 4

RP -HP L C

S -1 3 5

S -1 3 6

L i q W a s t e 7

S -1 3 9

S -1 4 0

S -1 4 1

W F I -3

P -3 0 / D F -1 0 3


M rE t OH

L i q W a s t e 8

S -1 4 5

S -1 4 6

S -1 4 7S -1 4 8

L i q W a s t e 9

S -1 5 0

S -1 5 1

E n z y m e s

S -1 5 3

W F I -4

L i q W a s t e 1 0

S -1 5 6

L i q W a s t e 1 1

S -1 5 8

S -1 5 9S -1 6 0

S -1 6 1

W F I -5

S -1 6 4

L i q W a s t e 1 2

S -1 6 5

S -1 6 6

S -1 6 7

L i q W a s t e 1 3

S -1 6 9

W F I -6

L i q W a s t e 1 4

S -1 7 2

S -1 7 3

S -1 7 4

S -1 7 5

L i q W a s t e 1 5

S -1 8 4

S -1 8 3

S -1 8 6

P ro d u c t

S -1 2 3

L i q W a s t e 1 7

Insulin Production Flowsheet

Fermentation Section

Primary Recovery Section

Reactions Section

Final Purification Section

P -3 8 / V -1 0 9

Bl e n d i n g / S to ra g e

S -1 1 6

E DT A S o l u ti o n S -1 3 8

S -1 4 2

P -1 0 / V -1 1 0

Bl e n d i n g / S to ra g e

S -1 1 8

T ri to n -X -1 0 0S -1 2 5

S -1 4 3

S -1 1 9

S -1 4 4

S -1 3 4

S -1 4 9

S -1 5 2

S -1 5 4

P -1 2 / V -1 1 1

V e s s e l P ro c e d u re

S -1 2 6

S -1 5 5

S -1 5 7

S -1 3 7

P -3 3 / D F -1 0 4


S -1 2 4

L i q W a s t e 1 6

S -1 6 8

S -1 6 2

process

36

Technology transferTechnology transfer

DiscoveryDiscovery GMP GMP ManufacturingManufacturing

DevelopmentDevelopment

••ScreeningScreening

••Bio Bio activityactivity

••ProofProof ofof conceptconcept

Lots Lots ofof freedomfreedom LittleLittle freedomfreedom No No freedomfreedom

Te

ch

no

log

yT

ech

no

log

yT

ran

sfe

rT

ran

sfe

r

Te

ch

no

log

yT

ech

no

log

yT

ran

sfe

rT

ran

sfe

r••ProcessProcess designdesign

••QualityQuality controlcontrol

••CharacterisationCharacterisation

••ProtocolsProtocols

••ReferenceReference standardsstandards

••PrePre--clinicalclinical testingtesting

••ScaleScale upup

••Phase IPhase I--IIIIII

••Batch recordsBatch records

••ValidationValidation

••QualityQuality assuranceassurance



37

Production Production andand processprocess controlcontrol

• Procedures and deviations

• Control procedures (identification)

• Calculation of yield

• Identification of equipment used duringproduction

• Sampling and analyses

• Time limitations during production

• Control of microbial contamination

• Rework

39

BuildingBuilding

40

RoomsRooms

• Design and characteristics of building

• Lighting

• HVAC – Heating, Ventilation, and Air Conditioning

• Plumbing

• Drains and waste

• Hygiene et toilette

• Sanitary conditions

• Maintenance



41

Clean Clean roomroom -- principleprinciple

ConditioningAir

HEPA filter

42

Clean Clean roomroom -- principleprinciple

SAS

43

LBVA LBVA manufacturingmanufacturing facilityfacility

Manufacturing

Quality Control

Airlock

Cleaning / sterilisation

Preparation solutions



44

GMP GMP FashionFashion

45

FlowFlow

decontamination

cleaning

sterilisation

46

MaterialsMaterials

$ $$

Buyer

Supplier

OK?

QualificationQuarantine inventory

Test

Rejectinventory

InventoryProduction Distribution

Receiving

Quarantine?

YES

YES

NONO



47

EquipmentEquipment

48

EquipmentEquipment

• Design, size, placement

• Construction of the equipment

• Cleaning and maintenance of equipment

• Automatic, mechanic andd electronic equipment

• Filters for liquid filtration

49

General cleaning considerationsGeneral cleaning considerations

• Use of material that is inert (low attachment of soil)

• Use of smooth materials

• Avoiding difficult to reach locations such as• Appendices that stick out

• Crevices

• Dead legs



50

LikeLike a a mirrormirror

51

Spray ballsSpray balls

52

Assays to verify effective cleaningAssays to verify effective cleaning

• Rinse water:• conductivity

• pH

• TOC

• Endotoxin

• Bioburden

• Surface:• Visual check

• Protein swab



53

Sterilization Sterilization –– the reasonthe reason

54

Factors determining thermal deathFactors determining thermal death

• The resistance of the present microorganisms to heat

• The temperature the contaminants are exposed too

• The time they are exposed to high temperature

• The effectiveness of the heat transfer

55

BioreactorBioreactor controlcontrol

heating

cooling

T

DO

Air/O2

CO2pH

acidbase

P AF

Anti foam

Nutrients

M

• Temperature

• pH

• Oxygen• Air/oxygen

• Agitation

• Pressure

• Agitation

• Nutrients

• Pressure

• Foam



56

ProgramsPrograms

• Preventive Maintenance

• Calibration

57

GMP means controlGMP means control

Quality Quality SystemSystem

58

How to controlHow to control

Methods of control

�Analyses

�

�

�

Monitoring

�Personnel

��Equipment

�Materials

��Building

��Process

ValidationTrainingCalibrationTesting

Quality Contol

Laboratory



59

QualityQuality Control Control LaboratoryLaboratory

• Independant

• Analyses (Raw materials, bulk, product andpackaging)

Sampling

Analyses

Measurements

Reports

• Environmental control (water, air, gasses)

• Investigations of out of limit results

• Stability

60

ValidationValidation

The documented act of demonstrating that any procedure,

process, and activity will consistently lead to the

expected results. Includes the qualification of systems

and equipment.

Validation ≠ GMP

Validation ⊆ GMP

61

Validation of a coffee machineValidation of a coffee machine

User User RequirementsRequirementsspecificationspecification

EngineerEngineer

Functional specification:•Heat water

•Transfer water to coffee…

Design specification:•Element of 750W•Reservoir of 1 L…

Validation

Installation Qualification

�Element of 750W?

�Reservoir of 1L?

OperationQualification

�Is water heated?

�Is water transfered?

Performance Qualification

�Does it makecoffee?

I wantcoffee



62

ProcessProcess validationvalidation

• Phase I: controlled process

• Phase II: process more controlled

• Phase III: process validated

63

ExampleExample: : presencepresence ofof virusvirus

• Phase I: sampling of each batch to prove absence ofvirus

• Phase II: sampling and validation of some process stepswith limited number of model viruses.

• Phase III: validation that the purification processremoves several model viruses effectively (minimally a log7 reduction)

Testing Validation

64

ChangeChange

Impact ?

Change



65

FvL Frank van Lier Consultancy

QUESTIONS

[email protected]@gmail.com

Documents

351al - BCM6013 - BPF - 2011.ppt)esilrch1.esi.umontreal.ca/~syguschj/cours/BCM6013/2011/expression... · not enough: the whole organisation has to be compliant to GMP. • Not just