1-3 ManufacturingProcess ProcessValidation

7/26/2019 1-3 ManufacturingProcess ProcessValidation

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MANUFACTURING PROCESS AND VALIDATION

Rutendo Kuwana

Training workshop: Assessen! o" In!er#hangea$%e M&%!iso&r#e Me'i#ines( )en*a( A&g&s! +,,-


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

Finishe' Phara#e&!i#a% Pro'! Man&"a#!&ring

Manufacturing and marketing authorization

Pharmaceutical development

Formulation

Sites of manufacture

Manufacturing process

Manufacturing process controls of Critical steps and intermediates

Process validation and Evaluation


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Manufacturing site(s)

Name and street address of each facilit where an aspectof manufacture occurs including production! sterilisation!

packaging and "ualit control

# $locks and %nits should &e clearl stated

# 'ncluding an alternative manufacturers

Certificate issued & the Competent (R) according to

*+, Certification scheme for each site where a ma-or

step of manufacturing is performed

.alid /MP certificate 0ma not insist if inspected & *+,1


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4

De.e%open! o" an&"a#!&ring pro#ess

Pre2 formulation

Formulation

Pilot manufacture

'ndustrial Scale


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5


Relationship &etween method of manufacture and processvalidation data

Process should address the need and value of in processcontrols

Process evaluation and validation should -ustif reduction ofsome tests from routine


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S#a%e Up Da!a

%sed to generate information from la&orator through

pilot to production scale &atch

Evidence that scale up will not result in loss in "ualit

Should show that variations in &atch size will not

adversel alter FPP characteristics


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009! |

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Man&"a#!&ring pro#ess

In"ora!ion re/&ire'

Flow diagram critical steps # in2process controls

(escription of manufacturing3packaging! including

Scale

E"uipment & tpe 0e4g4 tum&le &lender1 5 working

capacit

Process parameters for steps! e4g4 time! temp! p+

Environmental conditions! e4g4 rel4 humidit for

hgroscopic FPPs4


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009" |

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Man&"a#!&ring pro#ess 0+1

Proposal for reprocessing # -ustified with data

Cop of master formula

$atch manufacturing record # real &atch

Sterile products # sterilisation steps and 3 or aseptic procedures

(escription of in2process tests

(ata for 6 7 full scale &atches to show achievement of

predetermined specifications


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Man&"a#!&ring pro#essCon!ro%s o" #ri!i#a% s!eps an' in!ere'ia!es

Critical steps

)cceptance criteria 0-ustified1

8est methods 0cross reference accepta&le1

'ntermediates isolated during process e4g ta&let cores in

film2coated ta&let production

)cceptance criteria 0-ustified if not Compendial1

8est methods 0cross reference accepta&le1


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009#0 |

Manufacturing Process Controls of Critical steps and

Intermediates

Manufacturing step Test Item Methods Acceptance criteria

After Step 1.1 Yield By weighing 99-110%


After Step 2.1.3 Yield By weighing 98-100%

After Step 2.2.3 Yield By weighing 98-100%

After Step 3.2 Appearance Visual inspection See table below

After Step 3.2 Thickness See table below

After Step 3.2 A!erage "ass #nhouse See table below

After Step 3.2 $ardness %ur. &h. See table below

After Step 3.2 'riability %ur. &h 1%

After Step 3.2 (isintegration ti"e %ur. &h 1)"in



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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009## |

Manufacturing Process Controls of Critical steps and

Intermediates

Tes! I!e 2,,3+4,g Ta$%e!s)verage Mass # 9aer : 421-;; 679-:mg

)ppearance Round! &iconve?! &ilaered ta&let@one laer is ellow coloured and ma

&e mottled! and the other one is whiteto slightl ellow! with a &reak line!engraved A/PA on one side! andA:BBA on the other side

8hickness ;4:2;4;mm

+ardness


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Process Validation and Ealuation

*$+ !alidation definition

The docu"ented act of pro!ing that any procedure, process, e-uip"ent,"aterial, acti!ity, or syste" actually leads to the epected results.

&rocess !alidationis the collection and e!aluation of data, fro" processdesign stage throughout production, which establishes scientific

e!idence that a process is capable of consistently deli!ering -ualityproducts

/S '(A


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!"

Pro#ess .a%i'a!ion 5 e.a%&a!ion

(ifferentiate &etween the following generics

New FPPs0new for manufacturer! not marketed et1

# FPPs that have &een newl developed & the manufacturer! though it will &e

a generic

# Full validation re"uired

Esta&lished FPPs

# 8he manufacturer has manufactured 5 marketed this FPP for "uite some

time

# Su&mit review of report for 6 :B recent consecutive &atches

Manufactured within the preceding year. If less than 10 batches, may extend the period to3 years

result/trend/statistical analysis discussion

!e"ected batches excluded # submit failure in$estigation


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*hat should be !alidated 0

D)n aspect of operation! including significant changes to the

premises! facilities! e"uipment or processes! which maaffect the "ualit of the product! directl or indirectl!

should &e "ualified and validated


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Purpose of Process Validation

Process validation is intended to esta&lish that the proposed

manufacturing process is a suita&le one and ields

consistentl a product of the desired "ualit4

i4e4 that the process is suita&le and under control


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009# |


.alidation is mandator for processes including all critical steps

8he aim is to show that critical steps are under control and lead

continuousl to the desira&le "ualit

E?amples of critical steps 0list non e?haustive1

mi?ing!

coating!

granulation!

emulsification!

non2standard sterilisation


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009#! |


#etails re$uired on first " production %atc&es

$atches

&atch num&er

&atch size

place and date of manufacture

&atch num&er of )P'0s1

ield

&atch purpose 0validation! sta&ilit! clinical trial 1

Process

e"uipment

process parameters

validation protocol4

Results

critical steps

in process control

finished product specification


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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009#" |

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Va%i'a!ion 6new7 pro'!

Con#&rren! 3 prospe#!i.e .a%i'a!ion 021

Concurrent validation

# Carried out during normal production

# First 7 production &atches 0prospective validation1

# 'n2process controls are set on outcome of validation

E?tensive sampling and testingduring process! for e?ample 0ta&lets1

# planned sampling on mi?ing 3 granulation stages for content uniformit 0low2dose FPPs 5 F(Cs G1

# ) large num&er of ta&lets for mass and3or content uniformit! hardness!

fria&ilit and even dissolution

%ampled according to plan during process

%tatistical analysis of results with conclusions

&o be within acceptance criteria


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Con#&rren! 3 prospe#!i.e .a%i'a!ion 0+1

Parenteral products! asepticall filled 0if terminal sterilization is notpossi&le1

# Filling ampoules with culture media! then

# 'ncu&ation and control of micro&ial growth

# 9evel of contamination H B4:I

Challenge e?perimentsto determine

# ro&ustness of process

# effect of material variations! such as particle size can &e carried out on

e?perimental &atches e4g4 sta&ilit of granulate over time

# Effect in case of unplanned stoppage


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'


Con#&rren! 3 prospe#!i.e .a%i'a!ion 081

9a&orator scale&atches 0small size1!# 8o support e4g4 formulation and packaging development

Pilot &atches# %sed e4g4 in sta&ilit and safet3efficac studies

# Size for oral solid dosage forms the largest of :BI of production scale or:BB!BBB units

Productions scale# For full validation and sta&ilit studies

# Scale2up 3 scale down after registration

'p to10#fold compared to the original batch si(e )minor amendment/change*


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092# |

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Pro#ess Va%i'a!ion Da!a

Compliance with FPP specifications alone inade"uate todemonstrate validation of processes and control over

process

Manufacturer ma not have completed formal validation

on production scale &atches

'mportant to link development and evaluation of

la&orator and pilot scale &atches! process development

and optimisation


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''


Pro#ess Va%i'a!ion S#hee3Pro!o#o%

8o &e used for applications where production scale&atches not et produced

8o outline the formal validation process to &e conducted

on production scale &atches 0at least 7 consecutive

&atches1

(ata should &e availa&le for verification post 2

registration


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'"


Pro#ess Va%i'a!ion S#hee3Pro!o#o% 0+1

'nformation re"uired

2 short description of the process including critical processing steps or parameters to &e monitored

2 FPP release specifications

2 (etails of analtical methods

2 'PC proposed and acceptance criteria

2 additional testing and analtical validation

2 sampling plan # where! when and how samples are taken

2 details of methods for recording and evaluating of results

2 proposed timeframe


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Pro#ess Va%i'a!ion Repor!

)fter validation

$atch analtical data

Certificates of analsis

$atch manufacturing records

Report on unusual findings! modifications or changes found necessar

with appropriate rationale

Conclusions

Significant deviations to &e informed to (R) and regulator approval

re"uired &efore implementation


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t&er re$uirements

For well2esta&lished processes3product

for the manufacturer # report on review of N98 :B &atches

manufactured in the past :> months


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Re.iew repor! "or es!a$%ishe' FPP sho&%' #on!ain a!

%eas! !he "o%%owing

9ist of reviewed &atches 2 &atch num&ers! manufacturing dates and &atch size4 )ndifferences from the pre"ualified3approved &atch size should &e clarified4

Review of starting materials 0active pharmaceutical ingredients 0)P's1 and e?cipients1 #list of sources 0)P'1! compliance with specifications

Review of primar packing materials used in the FPP! including reference to those fromnew sources4

) ta&ulation of $atch )nalsis data 0including in2process test results and finished product"ualit control results1 together with statistical and trend analsis where appropriate4

) review of all out2of2specification and related investigations! with indication of &atchesthat failed to meet specification0s1

) review of all deviations4

)ll changes carried out

Jualit2related returns! complaints and recalls4


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092! |

*lternaties

'f validation data 0on production scale &atches1 are notavaila&le su&mit

validation protocol!

commitment that validation report will &e su&mitted laterfor evaluation!

commitment that data will &e availa&le in case ofinspection!

commitment that *+, will &e informed of an significantdeviation4


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092" |

Ana%*!i#a% Me!ho's

Process knowledge depends on accurate and precisemeasuring techni"ues on starting material! intermediates

and finished product4

For data to &e of value the analtical tests must &e

scientificall sound

.alidated analtical methods are not re"uired during product

and process development activities4 8he methods should

however &e scientificall sound 0e4g4 specific! sensitive!accurate1! suita&le and relia&le for the specified purpose4


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Use o" ana%*!i#a% e!ho's 9 generi#s

linical &har"aceutical ethodsAt initial phase of phar"aceutical de!elop"ent

+o determine%ioaaila%ilit,in&ealt&, olunteers

+o deelop a sta%le andreproduci%le formulationfor t&emanufacture of %ioe$uialence-dissolution- sta%ilit, and pilot.

scale alidation %atc&es

.+o understand t&eprofile ofrelated su%stancesand to stud,sta%ilit,and start measuringt&eimpact of/e, product and

manufacturingprocessparameterson consistent 0PP$ualit,

At ad!anced phase of phar"aceutical de!elop"ent

+o proe%ioe$uialenceafter criticalariations to t&epre$ualified dossier

+o optimi1e- scale.up- and transfer asta%le and controlledmanufacturing processfor t&epre$ualification product

+o %e ro%ust- transfera%le- accurate-andprecisefor specificationsetting- sta%ilit, assessment-and 2C release of pre$ualified%atc&es

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1-3 ManufacturingProcess ProcessValidation