Welcome to my graphical Knowledge summary

Dussex Jean-Charles Via pizzamiglio,9 CH-6833 Vacallo JEAN@bluewin.ch

FROM IDEA TO APPLICATION

TQMS-1

Summary of system actors

TQMS-1

Presentation in Work breakdown structure style

TQMS-2

Procedure deviation process according to deviation criticality

PROCEDURE DEVIATION

Approved PDR

Impact

majorLOT

INVESTIGATION

BATCH RELEA

SEMinor

Other batches to be manufactured ?

Yes

Approved PDR

Attached to the MBR as manufacturing instruction

FOR PLANNED DEVIATION

CHR

Open a Change report or fill in already open CHR

Apply change

LIRdecision

IncludesPDR

references

7 56

121110

8 4

21

9 3

immediately

7 56

121110

8 4

21

9 3

Before batch releaseIn parallel

REJECTED

Examples of Processes Scenario

CHR

BATCH RELEAS

E

IncludesLIRreference

sCustomer

Reprocess

7 56

121110

8 4

21

9 3

ASAP

BATCH RELEA

SE

IncludesPDR

references

LIR

Report deviationAssess impact

on product quality

Wait until a reasonable number of minor changes are to be applied,

and or validation process occursNormally during annual review

process

Batch destination

and changes to be applied

are taken in LIR decision

TQMS-3

Process parameter design space

Design space

Rpoted in Batch card

Used for proces optimisation

Ensure product Quality

Recommended Process parameters

Working parameter range

MBR

CRIT

ICAL

PRO

CESS

PAR

AMET

ER

CRIT

ICAL

PRO

CESS

PAR

AMET

ER

Reported in DMF

Instruments calibration range

Process limit for product quality

Critical Critical

Development report

May be updated

Operational process

parameter

May be updated

Operational process

parameter

Significant process parameter

Significant process parameter

TQMS-4

Validation workflow

Development studies

Process and Product characterisation

Manufacturing equipment capability

Prior manufacturing Experience

Risk AssesmentDefine critical

product & Proces attributes

Define Critical and Key Operational

Paameters and their Ranges

Scientific Judgement

Process & ProductCharacterisation

Report(s)Process Development Report(s) Updated Process

Understanding

ProcessValidation

Master Plan

ProcessPotocols

Production Records

ManufactureConformance

Lots

ProcessValidation

Reports

OngoingProcess

Monitoring

PROCESS DESIGN PHASE

Process qualification

phase

Process development

Commercialisationphase

Link to QualificationActivities:

Equipmnt, Utilities,Facilities, raw Materials

Risk analysis

Filter dryer Failure Mode Effect Analysis-01

FMEA Number --->

Product / Service Identifier --->

Telephone #:

Process being analyzed --->

FMEA Revision Date------>

Core Team --->

Process activity Potential Failure Mode

Potential Effect(s) of Failure

Sev

Type

Potential Cause(s) / Mechanism(s) of

Failure

Fishbone Cause

Category

Occ

Current Process Controls - Prevention

Current Process Controls - Detection

Det

RPN

Recommended Actions

Responsibility & Target

Completion DateActions Taken

Sev

Occ

Det

RPN

powder suction do not suck block process 5 I Transfer line stopped method1

Backflush vibrate , repair or replace

None10 50

do not suck block process 5 I Sampler valve blocked

machine1

Backflush vibrate , repair or replace

none10 50

do not suck block process 5 I vacuum valve blocked

man1

Backflush vibrate , repair or replace

none10 50

do not suck block process5

I Vacumm pump out Fishbone Cause

Category3

Repair or replace pump

none10 150

do not suck block process5

I lump formed3

DE-lumper system+Back flush

No powder in sampler 10 150

do not suck block process 5 I Hole formed Hole at suction point

?3

main container stirred or vibrated

No powder in sampler 10 150

Hardware failures Pneumatic actuators leaks

Cross contamination risk for product and containement 10

Mechanical or pneumatical sealing

machine

1

located in the glove box

no powder sampled

10 100

Seal between valve and actuator leaks

Cross contamination risk for product and containement 10

Mechanical or pneumatical sealing

machine

1

located in the glove box

?

10 100

Eric Cartman (Operations Manager), Kenny (South Park Store Manager), Marge Simpson (Springfield Store Manager), Stan Marsh (pizza creation associate), Kyle Brovlowski (BPI associate), Mr. Garrison (purchasing and inventory manager), Mr. Hand (pizza creation associate), Chef (BPI Manager)

Filter dryer FMEA-01

as required

Email address:

DJCPrepared by --->

Original Date ---> 07.01.2011Powder transfer system Other relevant information ---> visio cause effect diagram

Filter dryer+powder tranfer system

Level of DetailFMEA Type

Design or Process Responsibility -------------> DJC

System Process Component / PartDesign FMEA Process FMEA Process Step

Risk analysis

Cause Effect Diagram: sampling sys. no powder transferred

Some concepts

Process transfer and Equipment qualification

Process transferEquipment Qual.

Personnel flow, room pressure and class

Example of Room layouts and symbols

C D N

Class

Personnel inTrafic zone

+++

++

+

---

--

-

Pressure

-20 pA

-10/-15 pA

--25/-30 pA

+25 pA

+25/-30 pA

+10/-15 pA

Some room characteristic

symbols

Personnel clothing steps

Personnel flow

Factory entrance

Factory personnel entry from 008 to corridor 022

IN Steps Symbol Local Description Status 1

007 Inizia la procedura d’entrata personale Personnel entry procedure start.

2

010 & 011 Toglie giacca, zaino etc… Mette scarpe per aree di servizio e commune a tutto lo stabile

Qui si segrega le vie per personale ufficio, laboratorio, magazzino etc..

il personale di produzione segue la via step 3 e succsessivi

PRODUCTION STAFF

Non-Production

Staff

Personnel flow

Class D surrounding area3

Corridor 012 & 013

Mette le calze di nylon (usa e geta) e le scarpe di produzione

4

012 & 013 lascia qui tutti gli ogetti non amessi in area produttiva. Mette I vestiti di produzione:

- pantaloni bianchi - Maglitta bianca - Camice bianco

Accede al corridoio 015 ed al Sas 018

ACCESS CONTROL 1AUTHORISEDPERSONNEL

ONLY

5

018 Desinfetta le mani, passa sas 016 ed accede ai corridoi di produzione 022 028, 029 , lift, 129, 128,121

6 Personnel is now able to travel in Class D corridors

and access to Sas entry of the manufacturing boxes

Personnel flow

Specific workplace in qualified roomPersonnel access to BOX 023

IN Steps Symbol Local Description Status 023-1

Enter to sas 023-A Smette il camice bianco.

023.2

From 023-A to 023 Indossa il camice verde Sovra scarpe e cuffia ?

023.3

Work in 023

Out steps Symbol Flow 023.4

From 023 to 023-A

023.5

023-A Smette il camice verde Sovra scarpe e cuffia ?

023.5

From 023-A to corridor

Indossa il camice bianco

Personnel is now able to travel in Class D corridors and access to Sas entry of the manufacturing boxes or to return to civil clothing area.

Factory planning-P26

Water system 090320

Pre-URS discussion for project definition

Chromatography system pre-layout

Pre-URS discussion for project definition

Chromatography system Project pre-layout phase 1

P and ID symbols 110303

Drawing symbols (CAD)

Filter dryer flow inversion static drying

Development and test of new drying concept/componentsFILTRATE VACUUM

SLURRYNITROGEN

1

<

NITROGEN

OUTLET VACUUM

°c2

OPEN VALVE

NITROGEN

OUTLET VACUUM

3

Load slurry

OPEN VALVE

NITROGEN

Transfer system

Final container

4

Dry

Move cake

Discard

In order to develop new concepts/components to be applied in filtering/drying applications, we test, using a simple PE Bucket:• New discarding valve (SAV)• New filter sinter plate• Pneumatic conveying of dried product.•New discarding cyclone

Well Done.

After results computing, we decide to proceed with integrations of the concept/components to the entire range of filters/dryers we are using or prototyping.

Filter dryer flow inversion drying tray model

Filter dryer-NEW study of critical contamination points

Filter dryer flow inversion static drying container

Filter dryer-NEW study of critical contamination points

E-2

P-18FilterWash

Vacuum oven

Filter and wash Transfer in drying container, Weigh Close ovenSample

Open and close oven

Vacuum ovenVacuum oven

Dry

Vacuum oven

FinishDrying

Vacuum oven

Remove from Oven, weigh and take sample

Transfer to final container

Close and clean final container

Product data label

Apply label, weigh….

Exit of the contaminated

area

Apply vacuum

Open valve

Product suction

Small pressure/equilibrate level

Close the valve

Stop or contain pipe end

P-24Appply vacuum Break vacuum

Open valve

Suction sampling

Apply vacuum

Close valve

Stop or contain pipe end

Continue drying/sampling

up to OK

Break vacuum

P-33

Conect final container

Conect final container

P-45

P-44

P-51

P-50

Product contained in dirty enclosureProduct contained in dirty enclosure

Product in contact with area areaProduct in clean enclosure

External enclosure not contaminated Minor risk of contaminationExternal enclosure contaminated Risk of contamination

AREA contaminated Risk of contaminationExternal enclosure not contaminated No contamination risk

Filter dryer flow inversion ancillary equipments

Schematic flow of drying operations

Further samplings, repeat the 5 above steps

At mounted container

Mount a new container

Loose a little bit sampling container

Sampling quantity OK

Sampling 1

Sampling Operation V1 V2 SAVV-1

V-2

SAV m

Sav, 2, 1

2,1, sav

Sequence

Disconnect the flushing connector

Disconnect V-1

Close V-1

Stop the lateral TC

Disconect the lateral TC onto the sampling tee

At decontamination OK

Fluch decontamination medium

At mounted flushing connector

The flushing connector

Decontamination / cleaningOperation V1 V2 SAV

m

Sav, 2, 1

2,1, sav

Sequence

Alternatively, depends of further planned operations, disconnect at the point wher flexible fit the SAV

Brouh the tee as is into a glove box in order to dismount it and decontaminate the superior part included the contaminated fi lter.

V-1

V-2

SAV

Note, the points of potential contamination can be covered by mounting a plastic bag as enclosure. The bag will be closed during the vacuum suction phase applied for

disconnecting operations. The bag enclosing the disconnected part is used as contamination barrer and will be removed only in a protected area (GB for high active,

laminar flow or other area according to product needs.

Filter Dryer modules with sampling

Filter 8 inch modified for integration in glove box model 2

Filter Dryer modules with sampling

Filter 8 inch modified for integration in glove box model 3ed2

Filter dryer DN150 based

Filter glass DN-150 with heating

FP-1

FP-2

FP-3

FP-4

FP-5

FP-2

FP-6

FP-7

ST-1

ST-2

V-1

V-2

Layout of filter dryer with in line heater unit.Integrated mass flow controller and flash heating assembly

Containment glove box-P13

Glass reactor units, skid mounted into glove boxes P-13

1499

85

6

1398 799

744

670

R4A R3AT6A R4BT6BR6B Gs1

PLAN

FACE

BOX-1BOX-2BOX-3

Containment glove box-P13

Reactor Skid and special vacuum line

R4A R3AT6A

BOX 3 Unit

IF2A

R4BT6BR6B

BOX 2 Unit

Gs1

Flex toG1/2” male

Containment for filtering/drying

Filter 10 inches in glove box, pre-layout

OPTIONAL STIRRED FILTER

STATIC FILTER

TOP VIEW

Containment area for biotech

Clostridium high contamination risk lab layout ed2

Surrounding area 1 P: +++

Surrounding area 2P: --

“Nursery”AreaP: ---

“Kitchen”P: +

Wall autocalve

Reactors areaP: ---

Product separation area?P: ---

Material and productsdecontamination area

P: ---

QC areaP: ---

RM non cotaminated in

P:++

Personnal Changing

room 1 in and out

P:++

Personal in changing room 2

P: +

Personal out decontaminati

ionP: ---

Personal out decontaminati

ion-2P: --

Product out decontaminati

ion 2P: +

Product out out 3P: ++

Intermediate Sas material and equipment

P: -Wall SAs

+++

++

+

---

--

-

Pressure

-20 pA

-10/-15 pA

--25/-30 pA

+25 pA

+25/-30 pA

+10/-15 pA

++++ ++

+---

-

--

++

--------- ------

+++

Automated micro powder dryer-P26

Layout -1 with one outlet candle filter

PL-1 Pneumatic lift PlC safety durig opening

P-1P-2P-3P-4P-5P-6P-7

SpargerPressure sensor

Reserve/Cip out?CIP port inGas out+ Pt100

P-6P-7

Internal TK 1-1/2”TC 1-1/2 or NW 32TC 1-1/2 or NW 32TC 1-1/2 or NW 32TC 1-1/2 or NW 32

Port Assigned to ConnectorMass flow + Heater+PLC

OVP+PLCSensor+PLC

CIPTC 1-1/2 or NW 34 or TKEventual sight glass+ lightEventual sampling port

Ancilliary

P-8 Product filling PlC safety durig opening

P-1

P-2

P-3

P-4

P-5

P-6

P-7

P-8

LISG

PI

.

°C

V-6 V4

V-1

Exhaust gas

CIP

Process N

2

V-7

V5

V-2

V-3

F-1

V-8

P-8P-7P-6P-5P-4P-3P-2P-1Item

Product fillingSampling or resserve portSigght glass and related lightGas out+PT100CIP in to sprayballReserve/CIP outPressure sensorSpargerAssigned to

PLC to mange signal ?Light to PLCPT-100 connected to PLC

Pressure sensor PLC connected to PLCCustom made with sinterDescription

P-28

P-28

CIP

V-8V-7V-6V5V4V-3V-2V-1

Valves

Process gas inGas outGas outProcess gas inProcess gas inCip INCip iNCip INAssigned to

Check valvePneumatic actuated membrane valvePneumatic actuated membrane valvePneumatic actuated membrane valvePneumatic actuated membrane valvePneumatic actuated membrane valvePneumatic actuated membrane valvePneumatic actuated membrane valveDescription

V-9

V-9 Gas out Check valve

?xx??X

FlowPLC

xxxxxxxx

PLC

x

MFC

Nitrogen heaterNH

P-36

PL-1CIP

MFCNHItem

Pneumatic lift?Mass flow controllerNitrogen heaterAssigned to Description

?xx

PLC

CIPP-72

Automated micro powder dryer-P26

Layout -4 brainstorming with customer technical staff

P-1

P-2

P-3

P-4

P-5

P-6

P-7

P-8

LISG

PI

F-2°C

V-6 V-4

V-1

Exhaust gas

CIP

Process N

2

V-7

V-5

V-2

V-3

F-1

CIP

V-9

V-8

MFC Nitrogen heater

NH

CIP

Dismountable with TC?Only if the bottom part will be of 1 welded pce, in this case about 10 dedicated filter funnels are nedeed

F-3

Supplemental Safetety filter

Valutate to perform back flush via a second sinter port instead of trough the sparger.

Study sampling

Various containers volume with the same head

Valutate using a stedim sartorius addition port

PAT ? For in process control

MikiA supply 1 KG fine lactose to allow Jean’s engineering of sampling unitB Send a layout of batch sequences

Study Linear gas inlet if varant with two outlet filters is selected

Manage CIP when filter is removed.

This flange must be used onto Muller drums and other containers from different volumes

Due to the use of pneumatic lift, plan different bottom distancers according to the drum height

Biosafeport sartorius

walter

walter

walter

walter

V-14

P-9

P-1

0V-10

V-11

P-163

V-12

V-13

Samplingtube

This vanne can be taked off after config modification

This vanne can be taked off after config modification

Reserve process analyse PAT E-58

E-60

P-124

AIR

Deaerator

P-123

V-47CE

TE

P-128 CIP return

P-122

E-59TE

P-121

V-48

P-125

Water supplyP-131

FEPE

P-120LE

CE

V-45 P-132

P-127

Che

mic

als

CIP Supply

V-49

V-46

P-119

P-133

P-130

Automated micro powder dryer-P26

Final Head configuration layout (decisional to establish URS)

Check v

Gas

he

atM

FC

Sampling system

Dryer loadport 8

Spargerport 1

CIPport 4

Gas outport 5Gas out

port 9

Gas Flow outport

V-9.0V-1.3

F-9.1

VC-9.1

PFC-9.0

NH-9.0

MFC-9.0

V-10.3

V-10.1

V-10.2

V-1.1

V-5.1V-9.1

V-5.2V-9.2

V-4.1

V-5.3

VC-5.1

F-5.1

F-5.2

PFC

V-8.1

V-8.2

V-8.3

V-8.4

Vac transsystem

10 valves ratti 3/4”3 valves ratti 1-1/2”

4-20mAor PT or K

4-20mA

4-20mA

4-20mAor OP

4-20mAPI

Port 2

????’

Port 11

Test guaflon Membrane

1 bal valve 1/4”2 ball valve 3/4”1 ball valve 1-1/2Ball valvesGhidin type 133www.4gghidini.i

4-20mAPI

Port 2-A

1 o 2 KWHeater 220 v

4-20mA°C

Temp switch on/off

4-20mA°C

OP: digital RS-485; Modbus RTU (Slave); Lab View-VI‘s available(for pressure and flow) Option: ProfiBus DP-V0, DP-V1

4-20mAor OP

Supplemental services to be controled:2 air actuators (con switch fine corsa)1 air actauator big for cover liftingEventualy 2 DC motors about 50w to 150 watt maxon 1-Q-EC Amplifier DECS 50/5

Gas flow in port

Outlet sinterMounting proposal

Outlet sinterValves and filters mounting proposal

Vortex Powder management

Powder management under vacuum

Vaccum system connected to sinter

Task-3 config Task-5 config

Transfer

.

Sampler

500 ml

1” ballvalveSampling

with SPE

OMALDA-45

OMALDA-45

TOP View Front

Model integrated in glove boxes, corrected after risk analysis FMEA

Basic model used to develop process

HELIX FLASH DISTILLATION

Liquid distillation modelN2 flow regulation

1 to20 L

1 to20 L

DISTILLATE

RESIDUE

RAW Product

•Inert material construction•No moving mechanical parts• temp range RT+10 to 300°C (for Glass Model)•Pressure range +0.5 to absolute vacuum• Product/°C contact 5-10 seconds for water equivalent viscosity• Typical use, separation of two fractions.•Can be series mounted for multi-fractions distillation.• Used to distillate thermo sensible products.

CLEVER

HELIX FLASH DISTILLATION

Melting solids distillation model

1 LPneumatic actuated powder feeder

IN-line Powder melting Heater

Residue

Distillate

•Adding the powder feeder and the in-line melting unit to the liquid distillation model; its possible to distillate melting solids wit the “Helix”• A proved application is purification of DTE.

BE SMART

PASS BOX

Final packaging of pharmaceutical / different rooms

CIP VENTURI BASED

RINSE STEP

E-80

E-82

P-260

AIR

Deaerator

P-228

V-104I-51

I-64

P-276 CIP return

P-272

E-91I-64

P-285

V-102

P-233

Water supplyP-283

I-54I-50

P-234I-66

I-51

V-86P-288

P-247

Che

mic

als CIP Supply

V-96

V-92

P-250

P-286

P-266

V-103

P-232

P-286

3

1

4

5

2

The separator tank (3) is filled trough one of the two separator tank waffer filling valves(1). The supply pump (2) draw the water from the tank (3) and deliver the solution to the process trough the discharge control valve (4) at the programmed flow rate. At the same time, solution is pumped trough the venturi eductor (5) and back into the separator tank (3) inlet, thereby ceating a vacuum at the CIP return connection. The high turbulence created within the circuit prevents settling of any solid and provides self cleaning of the system. The rinse step is followed ba drain step. Tipically, a serie of 3-4 rinse/drain steps are utilised for the final rinse proven by low conductivity at the Cip return connection.

CIP VENTURI BASED

DRAIN STEP

E-90

E-88

P-274

AIR

Deaerator

P-235

V-84I-55

I-48

P-290 CIP return

P-255

E-84I-48

P-251

V-94

P-246

Water supplyP-271

I-65I-59

P-253I-61

I-55

V-100 P-281

P-239

Che

mic

als CIP Supply

V-85

V-88

P-261

P-267

P-263

V-99

P-236

P-267

3

45

6

The discharge control valve (4) is closed and solution from the separator tank (3) is pumped trough the venturi eductor (5) and back into the separator tank (3) inlet, thereby ceeating a vacuum at the CIP return connection. Returning solution create a high-level condition in the separator tank (3) causing the drain control valve (6) to bleed solution to drain at the set flow rate until the process and the separator tank (3) are empty.

CIP VENTURI BASED

WASH STEP

The separator tank (3) Is filled trough one of the the two separator tank water fill valve (1). The supply pump (2) draws the water from the separator tank (3) and deliver the solution trough the process trough the discharge control valve (4) t the programmed flow rate. At the same time, solution is pumped trough the venturi eductor (5) and back into the separator tank (3) inlet, thereby creating a vacuum at the CIP return connection. he high turbulence created within the circuit prevents settling of any solid and provides self cleaning of the system. CIP solution temperatures are elevated using the a heater (7) in the recirculation loop. Chemical solutions (8) are injected into the highly turbulent separator tank (3) and controlled trough conductivity..

Bioreactor P&ID

30 LITER BIOREACTOR

½ gas OD 21.3 x1.6

½ gas OD 21.3 x1.6

Pneumatic valves

Vxxx

Incorrect rappresentation

Pne

umat

ic

valv

es

25 L

15 L

650

240

Project management flows in API processing

7901 custom manufacturing, customer requirements for VMP

work order

MBR-02-000-07901-09

Production process records

Batch record

batch record

RM withdrawal

CLEANING

End of campaign cleaning

Batch review

End of campaign cleaning report

Process validation

validation protocol

Validation report

MBR-02-000-07901-05

MBR

MBR

Production batch

7901 PRODUCTION PROCESS AND DOCUMENTS

CLEANINGVALIDATION

INSTRUCTIONPPI-1 startup

box cleaning

startup PPSOP-5

Equipment startup

Box entry box day check

campaign closure

CAMPAIGN DOCS

external contractor cleaning

PPI1 cleaningEntry

EQUIPMENT

Release methods

HPLC PurityAppearance

IR identification

HPLC DAD UV Identification

General, compendial based Product specifics

Transfers and packaging

IQ OQ monitoring

VCF: 3Customer validation requirements

End of campaign cleaning

Ca 250 g (humid)

Ca-1690 g*(Yield79.36%)

PPI-1 Production room Class: not required

Residual solvents

Silver X ray

External, compendial based

External, product specificParticle size (laser)

MBR-02-000-07901-01

MBR

Water

CA 1370 g *

Humid (the 708 g

dried)

Humid (the 708 g

dried)

Humid (the 708 g

dried)

1 batch manufactured in 3 portions

NCC, crusts

Not for saleCommercial

* indicative values only

Steroids Dedicated reaction and filtration unit

PPI-1 Production room Class: not required

IQ OQ

IQ OQ monitoring

strartup

Dried in Filter

Intermediate release

Notes: document version, reported weight are only indicative and subject to change according to process evolution

MBR-02-000-07901-05end of campaign cleaning

7901 VMP.vsd

7901 custom manufacturing customer requirements for VMP

Not required Required

A customer need to manufacture a new API for clinical trials Phase III.In order to fix the Validation requirements for this process, graphical representation was lay down

Project management flows in API processing

7901 graphical batch record test for presentation

Project management flows in API processing

7901 Graphical Equipment Configuration sheet

After Process batch record was defined, a graphical representation of required equipment configuration was lay down

Project management flows in API processing

7901 Graphical micronisation external supplier control form-1

Lot: FP-0790101-…………...

Lot: FP-0790101-………...

Lot: NCC……………...

Consigned Received Used Returned Check

Container: None

Labels:

……...

Labels

FP label

QC retainedsample

NCC

tare

Container

Sign/check

Lot: FP-07901/………...

Related documents

CRYSTALLINE LOT

COARA

ORDERMBROther

Specification and referencePVP

SOPOther

IPM Certificate

Packing and labelling part

Shipment and receipt of crystallyne

Carrier: ………………………………………..

Jet pharma consigned on: ……………………… AT: …………………………...

TR receipt NR: ………………………………….. Send on…………………By:…..………….

Micronisation and packaging

For milling and in-process control, add as documentation:A Copy of the micronisation reportB Copy of particle size analysis of crystalline, in-process control, and final productC Copy of monitoring for microbiological and particles monitoring of the micronisation equipment and box . D Copy of the certificate of analysis of the milling fluid (Nitrogen)E Copy of the particle size determination SOP.F Schematic drawing of the microniser and related box.G Maximum 10 days after consignment of the micronised product, results of microbiological analysisH Completed sections of this batch recordG Weighing table reporting each portion and related retained samples taken

Function Check DateOperator

Supervisor

d (0.90) < 5 µmSS-02-0000-07901-01

Function Check DateOperator

Supervisor

category N/A Material Brown HPDE Brown HPDE

Drum

Symbol

Standard. volume 100 mL 1000 mL N/A N/A Supplied by Sicor Sicor Jet pharma Jet pharma

Assigned lot Nr

N/A N/A

Container: ……..

Labels: ……...

……...

Container: None

Labels: ……...

Labels: ……...

Container: None

Labels:

……...

Analytical sample

QTY in grams……………...

Main quantity

QTY in grams……………...

Color code for sections to be completed by microniserColor code for sections to be completed by Manuf.

Rest of mill

Crystalline API will be Micronised by an approved external supplier.The form on left details theProduct shipment and receiving protocol page 1

Project management flows in API processing

7901 Graphical micronisation external supplier control form-2Manuf receipt

Receipt on

Check packaging page for containers and labels Check: ……….

Check: ……….

Y/N: ……….

Documentation as reported in Microniser part:

Y/N: ………. Check: ……….Copy of the micronisation report

Check: ……….

Copy of particle size analysis of crystalline, in-process control, and final product

M-Bial results on batch will be send later

Copy of monitoring for microbiological and particles monitoring of the micronisation equipment and box.

Y/N: ……….

Check: ……….

Check: ……….

Y/N: ……….

Y/N: ……….

WH: ……….

Copy of the certificate of analysis of the milling fluid (Nitrogen)

Date ……….

Manuf warehouse operations

Group all containers of product in specification and its retainedsample in a box and store the box with a quarantine label in

quarantine area

Log the product and complete withdrawing formsY/N: ……….

WH : ………….

QC: …………...

QA: ……….

Store and login crust container in NCCY/N: ……….

Number of containers: ……….

Number of containers: ………

Grams: ………………...

Number of containers: ……….

Lot :……………… .. Total grams: …………..

Lot :……………… .. Total grams: …………..

Manuf batch record pre-approval and notes

OK on: …………..

QC pre-approval OK on: ………….. QC: ……….

Notes: ……………………………………………………………………………………………………………

……………………………………………………………………………………………………………………….…………………………………………

…………………………………………………………………………………………………………………………………………………………………

Check: ……….Y/N: ……….Copy of the particle size determination SOP.

Check: ……….Y/N: ……….Schematic drawing of the microniser and related box.

Check: ……….Y/N: ……….Maximum 10 days after consignment of the micronised product, results of microbiological analysis

Check: ……….Y/N: ……….Completed sections of this batch record

Check: ……….Y/N: ……….Weighing table reporting each portion and related retained samples taken

Crystalline API will be Micronised by an approved external supplier.The form on left details theProduct micronisation and back receiving protocol page 2

Project management flows in API processing

7901 Graphical example, yield sheet

FP-01/019

488 g (68.9)

R

FP-01/019

540g (76.3)

RDCU out

FP-01/021

534.2473.4

926g (65.4)

905

Micro looseal included

24.7%

0790109-001057901-09

7901-05

0790101-001057901-01

7901 xxxxX-2001 7901 xxxxX-2005

Used in humid form2456.9 g

7901-05 reprocessing

0790105-00205

1575.5g (93.7%)

0790105-00105

1690.1g (79.36%)

1682 g

1567.5 g

Jet pharmaMic Mac

NCC crusts103g (11.7%)

FP-01/022?682g (75.3 %)

1372.0 g (85.5%)

NCC crusts

37.0 g (2.3%)

Miller loose5.3%

Lotto Mulino Fluido ProcessoP.Entrata P.MacinazioneFeed rate G.PartenzaN.Micro G micro YieldFP-01/022 Mc.50 GB ARIA 8.00 8.00 0.130 905.0 2 volte 682 75.35912

Micro looseal included

14.5%

Campaign C-18 Starting 78793 x 265= 795 g

xxxxxxnide1500 g

yield as micronised calculated on xxxxxnide

as starting: 91.5%

yield as micronised calculated on Cp-7879 as

starting 173%:

Process and Yield comparison between external suppliers performing micronisation