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Prequalification Programme: Access to Antimalarial, Antituberculosis andanti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality

Prequalification Programme: Priority ssential !edicines

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Good Manufacturing Practices Part II

3 Specific GMP topics:Premises, Documentation and Validation

Anton Norder, MScTechnical Officer

WHO EMRO 1stWorkshop on the WHO Prequalification

Programme: Priority Essential Medicines

!airo Egypt " and # $une %&

2

%& '(enue 'ppia

!H)1%11 *ene(a %#

+,it-erland

E)mail:nordera who.int

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Guidelines and references

.ooklet:

/uality 'ssurance of pharmaceuticals0 ' compendium of guidelines

and related materials0 olume % second updated edition0 *ood

manufacturing practices and inspection0 World Health Organi-ation

*ene(a %& *ood Manufacturing Practices for pharmaceutical products: main

principles0 WHO Technical Report +eries 2o0 3&4 %&&5 'nne6 70

*ood Manufacturing Practices: starting materials0 WHO Technical Report

+eries 2o0 4%5 133%0

8!H /#': *ood Manufacturing Practice *uide for 'cti(e

Pharmaceutical 8ngredients International Conference onHarmonizationhttp:99,,,0ich0org9cache9compo9%#")%7)10html
http://www.ich.org/cache/compo/276-254-1.htmlhttp://www.ich.org/cache/compo/276-254-1.html

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WHO Guidelines and references cont!d"

WHO *ood Manufacturing Practices: ,ater for pharmaceutical use0WHO Technical Report +eries 2o0 3%3 %&& 'nne6 5http:99,hqli;doc0,ho0int9trs9WHO

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Prequalification Programme: Access to Antimalarial, Antituberculosis andanti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable QualityPrequalification Programme: Priority ssential !edicines

Ho#e$er t%ere!s more GMP!s:

P8!9+ *MP @Pharmaceutical 8nspection !o)operation +chemeA:

,,,0picscheme0orgB adopted ;y many countries e0g0

European Cnion or partially @!anada 'ustraliaA

2ational *MPDs in many countries @e0g0 C+' @,,,0fda0go(A

!hina 8ndia .ra-il 'rgentina etc0A

8nternational !onference on Harmoni-ation @8!HA: ,,,0ich0org

'lso refer to 8+O e0g in cases of filter types in H'!s clean

room design risk management etc0
http://www.picscheme.org/http://www.fda.gov/http://www.ich.org/http://www.ich.org/http://www.fda.gov/http://www.picscheme.org/

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O$er$ie# of specific GMP topics to &e

co$ered in t%is presentation:

Part 1:

Premises in relation to ;uildings design equipment etc0

Part %:

Documentation

Part 5:

ua!i"ication and #a!idation

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Q C Ofces

Gowning

Canteen

Incoming

goods

Corridor

CorridorShipping

Corridor

Packaging

Weighing Processing

Filling

Raw

Materials

&

Packaging

Storage

Washing Machine

Shop

Finished

Prodcts

Storage

Corridor

!tilities and Ser"ices

Waste #reatment

Part ': Premises

Arri#a! o" %oods &isitors entrance 'or(ers entrance Shi)ment o" %oods

Materia! *!ow

Peo)!e *!ow

+one -!ean +one Pac(a%in%

+one -ontro!!ed

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12.11 / 12.36

Premises: specific areas

Note that s)eci"ic re0uirements are %i#en "or s)eci"ic areas

'ncillary areas @go,ning rooms toilets refreshment rooms

maintenance areas animal housing etcA

+torage areas

Weighing areas

Production areas

/uality control areas

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12.11 / 12.14

Premises: ancillar( areas

Rest and refreshment rooms separate from manufacturing and

quality control areas

!hanging ,ashing and toilet areas accessi;le and appropriate

num;ers

Maintenance ,orkshops separated from production ) if not possi;le

tools in reser(ed areas

'nimal houses ,ell isolated separate air handling and entrance

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T O 8 = E T +

' 8R

= O ! F

! ' 2 T E E 2

G ' ! T O R ! H ' 2 * E

R O O M

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Premises: )eceipt and storage of goods

Se)arate recei#in% and

dis)atch as Materials and

products protectedfrom weather

Area to c!ean incomin%

materia!s )ro#ided

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-!eanin% o" incomin%

containers

Cleaning with a cloth, or

duster

Cleaning by using a vacuum

cleaner

Use of air curtains and air

tunnels

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12.15, 12.16


+torage areas of sufficient capacity

Orderly storage of categories of materials and products

+eparate and segregated areas: starting materials packaging

materials intermediates ;ulk finished products quarantined

released reIected returned and recalled products and materials

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12.16, 12.17


A))ro)riate tem)erature and re!ati#e humidit conditions

within de"ined !imits Provided, controlled, monitored and recorded

ood stora%e conditions clean dry and appropriate lights

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12.1$ / 12.2, 12.22


uarantine area clearly marked and access restricted

Se)arate sam)!in% area is the norm: no risk for contamination or

cross)contamination

Se%re%ated areas for reIected recalled and returned materials and

products

Sa"e and secure areas for highly acti(e radioacti(e materials

narcotics and other materials @risk of a;use fire e6plosionA

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12.21


Printed )ac(a%in% materia!s

Critical to ensure correct labelling of products

Special attention to sampling of printed pacaging materials

Special attention to safe and secure storage

!nsure compliance with specifications, prevent mi"#ups

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12.23

Premises: #eig%ing

Weighing operations in separated areas

'ppropriate design @see also *MP on H'!A

Pro(ision for dust control +mooth imper(ious dura;le easy)to)clean finishes

!leaning procedures and records

Jocumentation e0g0 +OPs logs and records

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Premises: #eig%ing

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)e*uirements on premises:

Desi%n

Walls floors ceilings ledges drains air supply dust e6traction

Pre#ention o" ui!du) o" dirt and dust to a#oid unnecessarris(s o" contamination

!leaning programme appropriate cleaning cleaning records ""ecti#e c!eanin% and disin"ection

!hoice of materials and chemicals (alidation

Drains / )re#ent ac("!ow

Protection "rom insects, irds, #ermin and weather from receipt of ra, materials to dispatch of released product

12.2, 12.3, 12.7, 12.9, 12.29

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Design of premises:

'a!!s, "!oors, cei!in%s /

smooth and eas to

c!ean

No !ed%es or areas

where dust canaccumu!ate

Pre#ention o" ui!du)

o" dirt and dust to

a#oid unnecessar

ris(s o" contamination

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12.24

Premises: production areas

Minimie ris( o" crosscontamination

$edicated and self#contained facilities for some products such ashighly sensitizing materials %e&g& penicillins' or biologicalpreparations %e&g& live microorganisms'

Separate facilities for other products such as some antibiotics,hormones, cytoto"ic substances

(on#pharmaceuticals normally not in the same facility, e&g&pesticides, herbicides

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12.32, 12.26, 12.31


8aout in accordance with se0uence o" )roduction

A))ro)riate c!ean!iness !e#e!

Ade0uate wor( and in)rocess stora%e s)ace

9rder! and !o%ica! )ositionin% o" e0ui)ment minimizes ris of contamination, mi"#ups and missing

production steps

S)ecia!! desi%ned areas "or )ac(a%in%

8aout to a#oid mi:u)s and crosscontamination

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12.27


Startin% and )ac(a%in% materia!s, intermediates and u!(e:)osed to en#ironment Interior surfaces %walls, floors, ceilings' ) smooth, free from

cracs and open *oints (o shedding of particles !asy and effective cleaning permitted

Disin"ection i" needed

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12.2$, 12.2


Desi%n o" )i)ewor(, !i%ht "ittin%s, and #enti!ation )oints / norecesses that are di""icu!t to c!ean

Access "or maintenance "rom outside )roduction areas

Drains o" ade0uate sie, and e0ui))ed to )re#ent ac("!ow

9)en channe!s a#oided

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12.3


""ecti#e #enti!ation with aircontro! "aci!ities

;nc!udin% "i!tration o" air to asu""icient !e#e! to )re#entcontamination and crosscontamination / a!so e:terna!

en#ironment -ontro! o" tem)erature and

re!ati#e humidit wherenecessar

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16.10 - 11

+$oiding cross contamination

S)ecia! )recautions shou!d e ta(en to )re#ent %eneration anddissemination o" dust

Pro)er air contro! / su))! and e:traction, suita!e 0ua!it

Due to uncontro!!ed re!ease o" dust gas particles (apours sprays organisms residue

insects

Dedicated and se!"contained areas "or =i(e (accines =i(e ;acterial preparations !ertain other ;iological materials

Penicillin products 16.12(a)

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16.12(b)

+$oiding cross contamination cont!d"

-am)ai%n )roduction Separation in time

+ollowed by appropriate cleaning

alidated cleaning procedure

&enti!ation sstems and air!oc(s -ppropriately designed ventilation system with air supply and

e"traction systems

Supply or incoming air should be filtered

.ecirculation of air versus /001 fresh air supply

Proper airflow patterns

Pressure differentials -ppropriately designed airlocs

16.12 (c and d)

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16.12(e)


-!othin%

Protection of operator and product

+it for its intended use

Highly potent products or those of particular ris # need for

special protective clothing

Personnel should not move between areas producing different

products

2arments need to be cleaned

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16.12(f, h and i)


-!eanin% and decontamination Procedure for removing soil and dirt

.emove all cleaning chemical residues or disinfectant residues

.emove and3or reduce micro#organisms

alidated %nown effectiveness of the procedure'

Use cleanliness status labels 4est for residues

-!osed )rocessin% sstems

+or e"ample5 totally enclosed water purification systems

4ans fitted with appropriate filtration # without removable lids

Present special cleaning difficulties, sometimes useclean#in#place %CIP' 16.12(g)

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Sanitation in production operations

'or("!ow designed to avoid potential contamination

Access

to production areas restricted to authorized personnel

direct operators, 6C staff, warehouse staff, maintenance

personnel, cleaners the more critical the area # fewer number of persons there

Simu!taneous o)erations

not permissible to process different products in different areaswith a common ventilation system

permissible to carry out secondary pacaging activities for

different products within a pacing hall with ade7uate physicalseparation

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Sanitation in production operationscont!d"

Area c!earance chec(s Process o" chec(in%

all materials and documentation from the previous batchremoved

all plant and e7uipment thoroughly cleaned and appropriatestatus labelling

checlist useful =he area c!earance chec( shou!d e carried out two )ersons

between batches of same product, acceptable for both checsto be carried out by production personnel

for product changeover, second chec carried out by 6C staff

all checs carried out in accordance with written S8P andresults recorded on the batch documentation&

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-g- line clearance in pac.aging

';sence of all materials

from pre(ious run including

printing masters

8ncludes checks on

materials and components .atch num;er

E6piry date

Printed packaging material

including cartons leaflets

foil 0 0 0

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-!eanin% and c!eanin% #a!idation degree of cleaning depends on whether consecutive batches are

of same or different product

-hec( c!eanin% a%ent is "u!! remo#ed

;" )ossi!e hot water a!one used "or c!eanin% all cleaning and disinfecting solutions carefully prepared and

e"piry dated

*or steri!e )roducts *ina! rinse with )uri"ied water, or water "or

in>ection

*u!! records (e)t

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Maintenance and re)air

activities inevitable in manufacturing area

Should present no ris to product

'hene#er )ossi!e, a!! )!anned maintenance outside norma!

o)eratin% hours

mer%enc wor( in wor(in% area "o!!owed thorou%h c!ean

down and disin"ection e"ore manu"acturin% recommences

Area c!earance -

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/asic Principles on premises in GMP

=he tem)erature and

re!ati#e humidit shou!d e

contro!!ed, monitored in

accordance with an S9P,

and the resu!ts recorded.

=he !imits shou!d e

a))ro)riate accordin% to

the materia!s stored and

)roduct )rocessed

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12.6

Premises: maintenance

-are"u! maintenance done

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12.33, 12.34

Premises of 0ualit( 1ontrol 2a&s

- !aoratories shou!d e se)arate "rom )roduction areas

Se)arate areas "or io!o%ica!, microio!o%ica! and radioisoto)emethods

Suita!e desi%n with su""icient s)ace to a#oid mi:u)s andcrosscontamination

Suita!e s)ace "or stora%e sam)!es, re"erence standards,so!#ents, rea%ents and records

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Part : Documentation

O;Iecti(es

1. =o re#iew %enera! re0uirements "or documents

2. =o re#iew s)eci"ic re0uirements "or each document

3. =o consider current issues a))!ica!e to our countries

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15.1

Documentation

ssentia! )art o" the A sstem, "or a!! as)ects o" MP Pur)ose o" documentation

$efines specifications and procedures for all materials andmethods of manufacture and control

!nsures all personnel now what to do and when to do it !nsure that authorized persons have all information necessary for

release of product !nsures documented evidence, traceability, provide records and

audit trail for investigation !nsures availability of data for validation, review and statistical

analysis

Desi%n and use

$epends upon manufacturer Some documents combined into one, sometimes separate

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Documentation

D t ti

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'h are documents so im)ortant?

-ommunication

-ost Audit trai!

Documentation

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15.2

Documentation: general principles

Documents shou!d e

$esigned, prepared, reviewed, distributed with care

-pproved by appropriate responsible persons

-om)! with mar(etin% authoriation

Desi%n o" documentation im)ortant

8oo( at the St!e o" the document

Instructions in the imperative

Short sentences preferred to long sentences

D l l !d"

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15.4

Documentation: general principles cont!d"

!ontents of documents should ;e clear @easy to understandA and

include e0g0

4itle, nature, ob*ective or purpose

=ayout in orderly fashion

Easy to ;e filled in and checked !lear and reada;le including copies made

2o errors if master documents are copied for ,orking documents

D i l i i l !d"

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15.5

Documentation: general principles cont!d"

Documentation contro!

Regular re(ie, of documents

Fept up to date @currentA ) amended

+uperseded documents remo(ed and not used

$istribution and retrieval of documentation

Retention time for superseded documents

D t t i d t

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15.6 15.8

Data entr( in documents:

!lear reada;le and indeli;le

Jesign to allo, for sufficient space for entries

!hanges to entries: signed, dated and reason given

original entry still readable Entries at the time of action

'll significant actions recorded tracea;le

D t t i d t

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15.9

Data entr( in e4documents:

Electronic data processing systems photographic systems or other relia;lemeans:

+ystems require +OPs and records

'ccuracy of records checked

'uthori-ed persons ) access and changes

Pass,ord controlled

Entries checked .atch records stored electronically:

Protected 9ac#up transfer, e&g& magnetic tape, microfilm, paper print#outs

Records kept 1 year after e6piry date of product

Jata readily a(aila;le during retention period

Diff t t f d t

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Different t(pes of documents

=a;els

+pecifications and testing procedures

Master formulae and instructions

.atch processing and ;atch packaging records

+tandard Operating Procedures @+OPsA

Records

Stoc control and distribution records

=og ;ooks

Other documents K

2a&els

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15.10

2a&els

What must ;e la;elledL Containers, e7uipment, premises

=a;el informationL Clear, unambiguous, company

format Intermediates and bul products

!olours can ;e used e0g0 green@acceptedA red @reIectedA

Jifferent types of la;els e0g0cleaning status production stagestatus of materials

Other types of la;elsL

Specifications

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15.14 - 15.17

Specifications

'uthori-ed appro(ed signed and dated Starting, pacaging materials and finished products5 include tests

on identity, content, purity, 7uality Intermediates and bul :ater, solvents and reagents

/! /' or documentation centre

Periodic re(ie,

!ompliance ,ith current pharmacopoeia

Pharmacopoeia reference standards and spectra a(aila;le

Specifications: Starting and pac.aging

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15.18 -15.19

Specifications: Starting and pac.agingmaterials

8nclude:

2ame @e0g0 822A and internal code

Pharmacopoeia @if applica;leA

/ualitati(e and quantitati(e requirements and limits

Other data may include:

+upplier

+ampling procedure or reference

+torage conditions precautions

Retest date

Specifications: 5inis%ed products

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15.21

Specifications: 5inis%ed products

8nclude:

2ame and code reference

2ames of acti(es @e0g0 822A

Gormula

Josage form package details

Reference to sampling

/ualitati(e and quantitati(e requirements and limits

+torage conditions and precautions

+helf life

Production documentation

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15.22 15.30

Production documentation

Bu!( manu"acturin%

Master formulae

9atch Processing .ecords

Pac(a%in%

Pacaging instructions

9atch Pacaging .ecords

The Maste f!"#$ae and the %ac&aging inst#cti!ns ae the c!nnecti!nd!c#"ent bet'een Ma&eting #th!iati!n, *+ecificati!ns and the

act#a$ ec!ds

Documentation

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Documentation

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Standard Operating procedures SOPs"

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Jescri;e one particular process in detail

Required for a lot of acti(ities mentioned in WHO chapter 1

Many other acti(ities outlined else,here in *MPs also require

+OPs

+OPs are non);atch related

'uthori-ation

Periodic re(ie,

ersion management

!lear instruction no am;iguities 15.31 15.48


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Part 3: 0ualification and Validation

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0

De"initions

a$idati!n

'ction of pro(ing in accordance ,ith the principles of *MP that any

procedure process equipment material acti(ity or system actually

leads to the e6pected results

#a$ificati!n

'ction of pro(ing that any premises systems and items of equipment

,ork correctly and actually lead to the e6pected results

@alidation usually incorporates the concept of qualificationA$!ssa/

S(stem life c(cle:

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( (

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Desi%n ua!i"ication DE: documentary e(idence that apremises equipment or process has ;een desi%nedinaccordance ,ith *MP requirements

;nsta!!ation ua!i"ication ;E: documentary e(idence that apremises equipment or process has ;een ui!t and insta!!edinaccordance ,ith *MP requirements

9)erationa! ua!i"ication 9E: documentary e(idence that apremises equipment or process o)eratein accordance ,ith*MP requirements

Per"ormance ua!i"ication PE: documentary e(idence that a

specific process ,ill consistently produce a product meeting itspre)determined specifications and quality attri;utes 4.3

0ualification and Validation

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Principle

ua!i"ication and #a!idation shou!d e done in accordance with an

on%oin% )ro%ramme

Initial 7ualification and validation

-nnual review

Maintain continued #a!idation status

Po!ic descried in re!e#ant documentation, e.%. 0ua!it manua!, or

&a!idation Master P!an4.5, 4.6

6(pes of $alidation documentation

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alidation Master Plan @MPA: policy responsi;ilities management of

(alidation process etc0

alidation protocols

alidation reports

+tandard Operating Procedures @+OPsA

Validation Master Plan VMP"

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'ppro(al page and ta;le of contents

8ntroduction and o;Iecti(es

Gacility and process description

Personnel planning and scheduling

Responsi;ilities of (alidation team mem;ers

Process control aspects Equipment apparatus processes and systems qualified (alidated

and to ;e qualified or (alidated

'cceptance criteria

Jocumentation e0g0(alidation protocols and reports

+OPs

Training requirements and other elementsK

)e*uirements to Validation documentation

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!learly defines responsi;ility of performing (alidation !onducted in accordance ,ith predefined appro(ed (alidation

protocols !onducted in accordance ,ith predefined appro(ed acceptance

criteria Recorded results and conclusions presented in ,ritten (alidation

reports prepared and stored Processes and procedures should ;e esta;lished on the ;asis of

these results Premises utilities equipment and processes !ritical importance and particular attention paid to (alidation of:

-nalytical test methods

-utomated systems Cleaning procedures 4.7 4.11


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nne 6

WHO References

ood manu"acturin% )ractices MPE %uide!ines on the

#a!idation o" manu"acturin% )rocesses

&a!idation o" ana!tica! )rocedures used in the e:amination o")harmaceutica! materia!s

7ample of priorities for process $alidation

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=)e o" )rocess

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A 0ua!i"ication or #a!idation )rotoco! ma contain

8b*ectives of the validation and 7ualification study

Site of the study .esponsible personnel $escription of the e7uipment

S8Ps

Standards Criteria for the relevant products and processes


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A 0ua!i"ication or #a!idation re)ort shou!d re"!ect the e!ements

o" the )rotoco!, and ma contain e!ements such as:

4itle

8b*ective of the study

.eference to the protocol

$etails of materials, e7uipment, instruments, personnel

Programmes and cycles used

$etails of procedure and test methods

etc&

Possi&le pro&lems in 0ualification and

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pValidation

=ack of time

=ack of personnel

=ack of e6perience and kno,ledge

!hanges to the process

Prospecti(e (ersus retrospecti(e (alidation

=ack of documentation infrastructure

=ack of implementation of (alidation

Poorly designed documents

Some GMP topics not co$ered toda(:

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&endor e#a!uation

Personne!

=rainin%

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