Member of Pharmaceutical

Inspection Cooperation

Scheme

INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC INTRODUCTION TO ASEPTIC

DISPENSING : DISPENSING : DISPENSING : DISPENSING : DISPENSING : DISPENSING : DISPENSING : DISPENSING :

1.1.1.1.1.1.1.1. PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS PIC/S GPP STANDARDS

2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN 2. CLEAN ROOM DESIGN & & & & & & & &

REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS

Ministry of Health, Malaysia

1

WHO Collaborating Centre

For Regulatory Control of

Pharmaceuticals

MS ISO 9001:2008 Certified

REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS REQUIREMENTS

ASEPTIC DISPENSING COURSE 2011ASEPTIC DISPENSING COURSE 2011ASEPTIC DISPENSING COURSE 2011ASEPTIC DISPENSING COURSE 2011

26 APRIL 201126 APRIL 201126 APRIL 201126 APRIL 2011

MOHD NASRUL MOHAMAD NOOR

PHARMACEUTICAL SERVICES DIVISION

- Background- Established Legal Framework & PIC/S GPP

Standard- Clean Room : Design & Requirements

OUTLINE PRESENTATION :

- Clean Room : Design & Requirementsi) Policyii) How Do We Know A Room Is A Clean Room

or Not?

2

BACKGROUNDBACKGROUNDBACKGROUNDBACKGROUNDBACKGROUNDBACKGROUNDBACKGROUNDBACKGROUND

3

BACKGROUNDBACKGROUNDBACKGROUNDBACKGROUND

� Basic approaches for sterile preparation :

�TERMINAL STERILISATION :

Filling and sealing the product into itsfinal container then sterilising itfinal container then sterilising it

�ASEPTIC PREPARATION :

Sterilisation of a product at some earlierstage before its filled/packed thencarrying out further processing/fillinginto sterile container using aseptictechnique and taking asepticprecautions 4

MALAYSIAN HOSPITAL MALAYSIAN HOSPITAL MALAYSIAN HOSPITAL MALAYSIAN HOSPITAL

PHARMACIESPHARMACIESPHARMACIESPHARMACIES

SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :SCENARIO AT PRESENT :

ASEPTICALLY PREPARED ASEPTICALLY PREPARED ASEPTICALLY PREPARED ASEPTICALLY PREPARED

PRODUCTSPRODUCTSPRODUCTSPRODUCTS

5

ASEPTIC PREPARATION IN MALAYSIAN HOSPITAL ASEPTIC PREPARATION IN MALAYSIAN HOSPITAL ASEPTIC PREPARATION IN MALAYSIAN HOSPITAL ASEPTIC PREPARATION IN MALAYSIAN HOSPITAL PHARMACIESPHARMACIESPHARMACIESPHARMACIES

Risks associated with aseptic preparation of Risks associated with aseptic preparation of Risks associated with aseptic preparation of Risks associated with aseptic preparation of

medicines:medicines:medicines:medicines:medicines:medicines:medicines:medicines:

(a) Medication Errors(a) Medication Errors(a) Medication Errors(a) Medication Errors

(b) Microbiological Contamination(b) Microbiological Contamination(b) Microbiological Contamination(b) Microbiological Contamination

7

(A) (A) MEDICATION MEDICATION

ERRORSERRORS

1. Can result in patient mortality and morbidity & need to be prevented

2. Frequently described medication errors result from:

i) The inability of medical & nursing staff to calculate dosescorrectly

ii) Incorrect drug product, dose & diluent selectionii) Incorrect drug product, dose & diluent selection

iii) Incorrect preparation method

iv) Absence of product labeling & documentation of parenteralprepared at ward or theater level

v) Incorrect route and method of administration(Cousins,D.H and Upton,D.R. How to prevent IV drug errors. Pharmacy in practice 1997; 7:310-312)

3. Inappropriate environment for the preparation of parenteral medicines inthe ward due to constant interruption

8

4 major sources of contamination associated with aseptically prepared products:

(B) MICROBIOLOGICAL CONTAMINATION(B) MICROBIOLOGICAL CONTAMINATION(B) MICROBIOLOGICAL CONTAMINATION(B) MICROBIOLOGICAL CONTAMINATION

�Airborne contamination

�Contamination by touch

�Surface contamination of components

�Contamination during storage

9

1111.... TheTheTheThe asepticasepticasepticaseptic techniquetechniquetechniquetechnique ofofofof thethethethe operatoroperatoroperatoroperator

� TrainingTrainingTrainingTraining ofofofof operatorsoperatorsoperatorsoperators isisisis aaaa criticalcriticalcriticalcritical aspectaspectaspectaspect ofofofof asepticasepticasepticasepticprocessingprocessingprocessingprocessing

3 Key Factors 3 Key Factors 3 Key Factors 3 Key Factors

10

2.2.2.2. AsepticAsepticAsepticAseptic workworkworkwork zonezonezonezone

3333.... OpenOpenOpenOpen orororor closedclosedclosedclosed proceduresproceduresproceduresprocedures

� ForForForFor openopenopenopen procedures,procedures,procedures,procedures, thethethethe standardstandardstandardstandard ofofofof environmentenvironmentenvironmentenvironment atatatat thethethethepointpointpointpoint ofofofof fillfillfillfill isisisis particularlyparticularlyparticularlyparticularly criticalcriticalcriticalcritical

ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & ESTABLISHED LEGAL FRAMEWORK & PIC/S GPP STANDARDPIC/S GPP STANDARDPIC/S GPP STANDARDPIC/S GPP STANDARD

11

ESTABLISHED LEGAL FRAMEWORKESTABLISHED LEGAL FRAMEWORKESTABLISHED LEGAL FRAMEWORKESTABLISHED LEGAL FRAMEWORK

Laws & Regulations

� Registration of Pharmacist Act 1951 (rev.1989)

� Poisons Act 1952 (rev.1989)

� Sales of Drugs Act 1952 (rev. 1989, 2006)� Sales of Drugs Act 1952 (rev. 1989, 2006)

- Control of Drugs & Cosmetic (Amendments) Regulations 2006

� Dangerous Drug Act 1952 (rev. 1980)

� Medicines (Advertisement & Sale) Act 1956 (rev.1983)

12

CONTROL OF DRUGS AND COSMETIC CONTROL OF DRUGS AND COSMETIC CONTROL OF DRUGS AND COSMETIC CONTROL OF DRUGS AND COSMETIC (AMENDMENT) REGULATIONS 2006 (AMENDMENT) REGULATIONS 2006 (AMENDMENT) REGULATIONS 2006 (AMENDMENT) REGULATIONS 2006

R7. (1) No person shall manufacture, sell, supply, import @ possess for sale any product unless :-

(a) the product is a registered product; and

(b) the person holds the appropriate license required & issued underthese Regulations

R15. Exemptions

Extraction from R15. (2) (b) & (3) :

Exemption for the purpose of dispensing

Extraction from R15. (6) :

Exemption can be given to ensure accessibility to patient

13

� Guides for Pharmaceutical Product Registration

� Guides for Traditional Medicines Registration

� Guides on GMP For Traditional Medicines

� Guides for Cosmetic Registration

� Guides on GMP For Cosmetics

� Guides for Good Storage Practice

ESTABLISHED GUIDELINES FOR REGISTRATION & ESTABLISHED GUIDELINES FOR REGISTRATION & ESTABLISHED GUIDELINES FOR REGISTRATION & ESTABLISHED GUIDELINES FOR REGISTRATION & LICENSINGLICENSINGLICENSINGLICENSING

� Guides for Good Storage Practice

� Guides for Reporting & Monitoring ADR

� Guides for Good Clinical Practice (GCP)

� Guides for Clinical Trial Import License

� Guides for Application to Conduct Clinical Trials

� Guides for Bioequivalence / Bio Avaibility Study

� PIC/S GMP Guides for Medicinal Products

14

PIC/S GPP

GUIDE?

CANADA

ARGENTINA ITALY

AUSTRALIA LATVIA

AUSTRIA LIECHTENSTEIN

BELGIUM LITHUANIA

CANADA MALAYSIA

CYPRUS MALTA

NETHERLANDS

CZECH REP. NORWAY

DENMARK PORTUGAL

ESTONIA POLAND

FINLAND ROMANIA

FRANCE SINGAPORE

GERMANY SLOVAK REPUBLIC

14141414THTHTHTH JANUARY 2002 JANUARY 2002 JANUARY 2002 JANUARY 2002 –––– MALAYSIA WAS MALAYSIA WAS MALAYSIA WAS MALAYSIA WAS ACCEPTED AS THE 21ACCEPTED AS THE 21ACCEPTED AS THE 21ACCEPTED AS THE 21STSTSTST MEMBER OF PIC/SMEMBER OF PIC/SMEMBER OF PIC/SMEMBER OF PIC/S

15

AUSTRALIA

GERMANY SLOVAK REPUBLIC

GREECE SOUTH AFRICA

SPAIN

HUNGARY SWEDEN

ICELAND SWITZERLAND

IRELAND UNITED KINGDOM

ISRAEL UKRAINE

USA

39 PIC/S 39 PIC/S –– Participating Authorities of 37 Countries @ January 2011Participating Authorities of 37 Countries @ January 2011

PIC/S [PHARMACEUTICAL INSPECTION PIC/S [PHARMACEUTICAL INSPECTION PIC/S [PHARMACEUTICAL INSPECTION PIC/S [PHARMACEUTICAL INSPECTION COCOCOCO----OPERATION SCHEME]OPERATION SCHEME]OPERATION SCHEME]OPERATION SCHEME]

� PIC/S Guide To Good Manufacturing Practice For Medicinal Products; PE 009-09; 1 September 2009

FOR PRODUCTSRegulated by NPCB

No. of Manufacturers = 234

� PIC/S Guide To Good Practices For The Preparation of Medicinal Products In Healthcare Establishments; PE 010-3; 1 October 2008

FOR PRODUCTSNo. of Manufacturers = 234

FOR

PREPARATIONSStarted since 2003

16

PIC/S GPP GUIDEPIC/S GPP GUIDEPIC/S GPP GUIDEPIC/S GPP GUIDE

CHAPTERSCHAPTERSCHAPTERSCHAPTERS BASIC REQUIREMENTSBASIC REQUIREMENTSBASIC REQUIREMENTSBASIC REQUIREMENTS

1111 QUALITY ASSURANCE QUALITY ASSURANCE QUALITY ASSURANCE QUALITY ASSURANCE

2222 PERSONNELPERSONNELPERSONNELPERSONNEL

3333 PREMISES & EQUIPMENTPREMISES & EQUIPMENTPREMISES & EQUIPMENTPREMISES & EQUIPMENT

4444 DOCUMENTATIONDOCUMENTATIONDOCUMENTATIONDOCUMENTATION4444 DOCUMENTATIONDOCUMENTATIONDOCUMENTATIONDOCUMENTATION

5555 PRODUCTIONPRODUCTIONPRODUCTIONPRODUCTION

6666 QUALITY CONTROLQUALITY CONTROLQUALITY CONTROLQUALITY CONTROL

7777 CONTRACTCONTRACTCONTRACTCONTRACT MANUFACTURE & ANALYSIS / MANUFACTURE & ANALYSIS / MANUFACTURE & ANALYSIS / MANUFACTURE & ANALYSIS / WORK CONTRACTED OUTWORK CONTRACTED OUTWORK CONTRACTED OUTWORK CONTRACTED OUT

8888 COMPLAINTS & PRODUCT RECALLCOMPLAINTS & PRODUCT RECALLCOMPLAINTS & PRODUCT RECALLCOMPLAINTS & PRODUCT RECALL

9999 SELF AUDITSSELF AUDITSSELF AUDITSSELF AUDITS

17

ANNEXESANNEXESANNEXESANNEXES SPECIFICSPECIFICSPECIFICSPECIFIC REQUIREMENTSREQUIREMENTSREQUIREMENTSREQUIREMENTS

1111 Guidelines on the Standard Required for the Sterile Preparation Guidelines on the Standard Required for the Sterile Preparation Guidelines on the Standard Required for the Sterile Preparation Guidelines on the Standard Required for the Sterile Preparation of Medicinal Productsof Medicinal Productsof Medicinal Productsof Medicinal Products(6 Sections)(6 Sections)(6 Sections)(6 Sections)

PIC/S GPP GUIDE [ANNEXES]PIC/S GPP GUIDE [ANNEXES]PIC/S GPP GUIDE [ANNEXES]PIC/S GPP GUIDE [ANNEXES]

2222 Guidelines on the Standard Required for the NonGuidelines on the Standard Required for the NonGuidelines on the Standard Required for the NonGuidelines on the Standard Required for the Non----Sterile Liquids,Sterile Liquids,Sterile Liquids,Sterile Liquids,Creams and OintmentsCreams and OintmentsCreams and OintmentsCreams and Ointments

3333 AnnexAnnexAnnexAnnex 3 ; Manufacture of Radiopharmaceuticals (Coming soon)3 ; Manufacture of Radiopharmaceuticals (Coming soon)3 ; Manufacture of Radiopharmaceuticals (Coming soon)3 ; Manufacture of Radiopharmaceuticals (Coming soon)

18

2) CLEAN ROOM : 2) CLEAN ROOM : 2) CLEAN ROOM : 2) CLEAN ROOM : DESIGN & DESIGN & DESIGN & DESIGN & DESIGN & DESIGN & DESIGN & DESIGN &

REQUIREMENTSREQUIREMENTSREQUIREMENTSREQUIREMENTS

19

INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION• What is a clean room?

AnAnAnAn areaareaareaarea withwithwithwith defineddefineddefineddefined environmentalenvironmentalenvironmentalenvironmental controlcontrolcontrolcontrol ofofofof particulateparticulateparticulateparticulateandandandand microbialmicrobialmicrobialmicrobial contaminationcontaminationcontaminationcontamination constructedconstructedconstructedconstructed andandandand usedusedusedused suchsuchsuchsuch aaaawaywaywayway asasasas totototo reducereducereducereduce thethethethe introduction,introduction,introduction,introduction, generationgenerationgenerationgeneration andandandand retentionretentionretentionretentionofofofof contaminantscontaminantscontaminantscontaminants withinwithinwithinwithin thethethethe areaareaareaarea

PIC/S GPP Chapter 3

Why do we need a clean room?• Why do we need a clean room?

� To protect product against particulate and microbialcontamination

� To provide a self-contained and safe working environment

� To prevent cross-contamination

� Critical for sterile products and aseptic processing

POLICYPOLICYPOLICYPOLICY� All sterile pharmaceutical preparations shall be produced in a qualified

clean room facilities designed and built in accordance to Good PreparationPractice (GPP) requirements

� CDR preparation facility shall be made available in each statestatestatestate hospitalhospitalhospitalhospital andandandandhospitalhospitalhospitalhospital withwithwithwith specialistspecialistspecialistspecialist

� Parenteral Nutrition preparation facility shall be made available in hospitalwith ICU,ICU,ICU,ICU, NICUNICUNICUNICU andandandand surgicalsurgicalsurgicalsurgical departmentdepartmentdepartmentdepartment

� Clean rooms shall be designed and built by experienced clean roomcontractors. The proposed layout plan, grades and control parameters shallbe submitted to the Pharmacy Practice and Development Division ofMinistry of Health for approval prior to the development of the facilities

21

POLICY…CONT.POLICY…CONT.POLICY…CONT.POLICY…CONT.

� Upon commissioning by the contractor, clean rooms and their majorequipment (laminar airflow cabinet and cytotoxic drug safety cabinet/isolator)shall be tested by an independent third party agent for confirmation ofcompliance to standards.

� The testing agent shall be accredited by appropriateappropriateappropriateappropriate accreditationaccreditationaccreditationaccreditation bodiesbodiesbodiesbodies suchsuchsuchsuchasasasas NationalNationalNationalNational AssociationsAssociationsAssociationsAssociations ofofofof TestingTestingTestingTesting AuthoritiesAuthoritiesAuthoritiesAuthorities (NATA(NATA(NATA(NATA ---- Australia)Australia)Australia)Australia) orororor NationalNationalNationalNationalThe testing agent shall be accredited by appropriateappropriateappropriateappropriate accreditationaccreditationaccreditationaccreditation bodiesbodiesbodiesbodies suchsuchsuchsuchasasasas NationalNationalNationalNational AssociationsAssociationsAssociationsAssociations ofofofof TestingTestingTestingTesting AuthoritiesAuthoritiesAuthoritiesAuthorities (NATA(NATA(NATA(NATA ---- Australia)Australia)Australia)Australia) orororor NationalNationalNationalNationalEnvironmentalEnvironmentalEnvironmentalEnvironmental andandandand BalancingBalancingBalancingBalancing BureauBureauBureauBureau (NEBB(NEBB(NEBB(NEBB ---- USA)USA)USA)USA)

� Clean rooms, unidirectional airflow cabinet and cytotoxic drug safetycabinet/isolators shall be maintained regularly according to approved plannedpreventive maintenance procedures.

22

HOW DO WE KNOW A ROOM IS CLEAN ROOM OR HOW DO WE KNOW A ROOM IS CLEAN ROOM OR HOW DO WE KNOW A ROOM IS CLEAN ROOM OR HOW DO WE KNOW A ROOM IS CLEAN ROOM OR NOT ?:NOT ?:NOT ?:NOT ?:

1. Design layout of premises

2. Building materials used

3. Critical parameters 3. Critical parameters

23

DESIGN LAYOUT OF PREMISESDESIGN LAYOUT OF PREMISESDESIGN LAYOUT OF PREMISESDESIGN LAYOUT OF PREMISES

� Premises and utilities for CDR Facility shallshallshallshall bebebebe separatedseparatedseparatedseparated fromNon-CDR Facility (for eye drops, IV admixtures and parenteralnutritions)

� The building design shall take into account the flow of the� The building design shall take into account the flow of thematerials, products and personnel.

� Personnel, equipment and work-in-process shall not be movedthrough areas in which other operations are running. Thisrequires that areas used for processing shall have separate accessfrom corridors and a one-way flow is preferable.

25

DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.

� A clean room facility shall have personnel changing rooms (forchanging and gowning), a component room, a CDR room and anarea for storage, receiving and distribution activities

� Buffer/staging room or a hatch shall be used for transferringmaterials (e.g. components, cleaning materials and equipment).If a one way flow facility is not possible, the buffer/staging roomIf a one way flow facility is not possible, the buffer/staging roomor hatch can be used for transferring materials and products outas well

� Apart from cleanliness, design of the CDR facility shall considerand fulfill the requirement of containment. This can be achievedby having a negative airlock adjacent to the CDR room.Depending on the layout design, this airlock can also be suitablylocated to contain the whole facility 26

DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.DESIGN LAYOUT OF PREMISES…CONT.� Air handling unit (AHU) and its room shall be dedicated. The air handling

system for CDR room and airlock shall not be re-circulated and shall be fittedwith an emergency push button for use during spillage

� There shall be two parts of personnel changing room. The second or final partof the personnel changing room leading into the CDR room shall be of the samegrade of the lattergrade of the latter

� Sink for hand washing can be fitted in the first or earlier part of the changingroom. The CDR/PN room shall not contain any sink or floor drains

� Dedicated air handling system shall be required for sterile preparation facilitiesand shall be fitted with alarms so that the working personnel are warned of anyfailure of the systems. The system shall be able to maintain 24 hours pressuredifferentials without cooling whenever the facilities are not in use

27

CLEAN ROOM GRADESCLEAN ROOM GRADESCLEAN ROOM GRADESCLEAN ROOM GRADESFOR ASEPTIC PREPARATIONFOR ASEPTIC PREPARATIONFOR ASEPTIC PREPARATIONFOR ASEPTIC PREPARATION

GRADEGRADE EXAMPLESEXAMPLES OF OPERATIONS FOR OF OPERATIONS FOR

ASEPTIC PREPARATIONSASEPTIC PREPARATIONS

A Aseptic preparation & filling

e.g. : LAF Cabinet

B An aseptic room or background

environment for Grade A

e.g. : CDR Room

C Preparation of solution to be filtered

e.g.: Comp. Prep. Room

D Handling of components after

washing

CLEAN ROOM DESIGNCLEAN ROOM DESIGNCLEAN ROOM DESIGNCLEAN ROOM DESIGN----Box Within a Box PrincipleBox Within a Box PrincipleBox Within a Box PrincipleBox Within a Box Principle----

GRADE D

Filter efficiency 95%, Max. particle count 3,520,000 per M3

Pressure +

GRADE C

Filter efficiency 99.995%, Max. particle count 352,000 per m3

Pressure ++

GRADE B

Filter efficiency 99.997%, Max. particle count 3520 per m3Filter efficiency 99.997%, Max. particle count 3520 per m3

Pressure +++

GRADE A

Max. particle count 3520 per m 3

Pressure ++++

Note:

•Grade A is a work station under a laminar air flow

•Grade B is an aseptic room or a background environment for Grade A

•Grade C and D are clean rooms of lower grades for less critical operations

Air

Movement

RECOMMENDED MINIMAL GRADES & MAJOR RECOMMENDED MINIMAL GRADES & MAJOR RECOMMENDED MINIMAL GRADES & MAJOR RECOMMENDED MINIMAL GRADES & MAJOR EQUIPMENTEQUIPMENTEQUIPMENTEQUIPMENT

WORKINGWORKINGWORKINGWORKING

ENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENT

BACKGROUNDBACKGROUNDBACKGROUNDBACKGROUND

ENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENT ENVIRONMENTENVIRONMENTENVIRONMENTENVIRONMENT

LFC GRADE A GRADE B

ISOLATOR GRADE A GRADE D

MAJOR EQUIPMENTMAJOR EQUIPMENTMAJOR EQUIPMENTMAJOR EQUIPMENT

• A cytotoxic drug safety cabinet or isolator (CDR cabinet/isolator) shall be used toensure maximum personnel protection. The cabinet and isolator used shall be of aGrade A air quality for the protection of product

• Appropriate measuring devices shall be installed for CDR cabinet or isolator such as :

� Pressure gauges for monitoring the pressure across the HEPA filters

� Down flow sensor for velocity

A limit window sash sensor shall be available to ensure negativity within CDR� A limit window sash sensor shall be available to ensure negativity within CDRcabinet

• Since the CDR/Non-CDR room shall not have a workbench, equipment installed(either cabinet or isolator) shall come with its own stands. There shall be sufficient

• A positive pressure unidirectional airflow cabinet or isolator shall be used forParenteral Nutrition and Eye Drop. For IV Admixture preparations, a negativepressure unidirectional cabinet or isolator shall be used to ensure maximumpersonnel protection

31

LAMINAR AIR FLOW CABINETS (LAFC)LAMINAR AIR FLOW CABINETS (LAFC)LAMINAR AIR FLOW CABINETS (LAFC)LAMINAR AIR FLOW CABINETS (LAFC)

� Positive Pressure

� Protect the product

� 2 types:� 2 types:a) Horizontal LAFCb) Vertical LAFC

� Used for:� TPN compounding� IV Admixture (not involving antibiotics)� Eye Preparations (not involving antibiotics)

HORIZONTAL LAFCHORIZONTAL LAFCHORIZONTAL LAFCHORIZONTAL LAFC

HEPA Filter

VERTICAL LAFCVERTICAL LAFCVERTICAL LAFCVERTICAL LAFCHEPA Filter at the top

BIOHAZARD SAFETY CABINETS (BSC)BIOHAZARD SAFETY CABINETS (BSC)BIOHAZARD SAFETY CABINETS (BSC)BIOHAZARD SAFETY CABINETS (BSC)

� Negative Pressure

� Provides personnel protection

� Various types of BSC

a) Class Ia) Class I

b) Class II – Type A, Type B1, Type B2

c) Class III – also known as isolator

CLASS I BSCCLASS I BSCCLASS I BSCCLASS I BSC

� Similar to fumehood

� Does not protect the productproduct

� Not suitable for aseptic preparation

CLASS II BSC TYPE ACLASS II BSC TYPE ACLASS II BSC TYPE ACLASS II BSC TYPE A

� Re-circulate approximately 70% of cabinet air through HEPA filters back into the cabinet

� The rest is discharged through a HEPA filter into the preparation room.

� Suitable for antibiotic preparation.

CLASS II BSC TYPE B1CLASS II BSC TYPE B1CLASS II BSC TYPE B1CLASS II BSC TYPE B1

� Re-circulate 30% of the cabinet air

� Exhaust the rest to the outside through HEPA filtersoutside through HEPA filters

� Suitable for CDR

� CDR cabinet should have carbon filter

CLASS II BSC TYPE B2CLASS II BSC TYPE B2CLASS II BSC TYPE B2CLASS II BSC TYPE B2

� Similar to Type B1 except that no air is recirculated

� Ideal

� Very expensive

CLASS III BSCCLASS III BSCCLASS III BSCCLASS III BSC� Totally enclosed with gas tight construction.

� The entire cabinet is under negative pressure

� Operations are performed through attached gloves. � Operations are performed through attached gloves.

� All air is HEPA filtered.

� May be used in CDR and antibiotic reconstitution.

� Movement is limited

Grade BGrade BGrade BGrade B

Grade CGrade CGrade CGrade C

Grade CGrade CGrade CGrade C

EXAMPLE OF CLEAN ROOM LAY-OUT 1

CDR Clean Room with CDR Cabinet

Grade BGrade BGrade BGrade B

Grade AGrade AGrade AGrade AGrade BGrade BGrade BGrade B

Grade BGrade BGrade BGrade B

Legend :

Personnel flow

Finish goods flow

Material flow

Grade BGrade BGrade BGrade B

Grade BGrade BGrade BGrade B

Example of Clean Room Layout 2 3

TPN

Grade CGrade CGrade CGrade C

Grade BGrade BGrade BGrade B

Grade CGrade CGrade CGrade C

Legend :

Personnel flow

Finish goods flow

Material flow

CDR with

Isolator

Grade DGrade DGrade DGrade D

Grade DGrade DGrade DGrade D

Grade DGrade DGrade DGrade D

Example of Clean Room Layout 3

Legend :

Personnel flow

Finish goods flow

Material flow

CONSTRUCTION REQUIREMENTSCONSTRUCTION REQUIREMENTSCONSTRUCTION REQUIREMENTSCONSTRUCTION REQUIREMENTS• Construction material should be non-shedding, non-porous

with smooth surfaces and resistant to microbial growtho ‘Sandwich partition’ (e.g. PU @ PS panel)

o Glass windows/doors with aluminium or stainless steel frames (double glaze type)

o Ceiling with ‘Sandwich partition’ (e.g. PU @ PS panel)

• All exposed surfaces (including floor) :• All exposed surfaces (including floor) :

o smooth, impervious, unbroken

o minimize shedding and accumulation of particles, microorganisms

o permit cleaning and disinfection

o no uncleanable recesses, ledges, shelves, cupboards, equipment

o sliding doors undesirable

o proper installation of pipes and ducts, no recesses, no unsealed openings

o shall be flushed-mounted, watertight, have no crevices and shall be cleanable (electrical outlets)

46

SANDWICH

PARTITION

CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.

� Bare wood, ledges and other unsealed surfaces shall be avoided inclean rooms.

� Adequate lighting shall be provided in all clean rooms (500500500500 ---- 600600600600lux)lux)lux)lux)

� Lights fixtures shall be flushflushflushflush----mountedmountedmountedmounted in the ceiling and sealed toprevent air leaks. It is preferable that they can be maintained andprevent air leaks. It is preferable that they can be maintained andserviced from above.

� Doors and windows shall have a hard, smooth, impervious finish andclose tightly and also fit flush with surrounding walls.

� All doors for clean rooms shall be fitted with interinterinterinter----lockinglockinglockinglocking systemssystemssystemssystems....

48

CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.CONSTRUCTION REQUIREMENTS…CONT.

Not AcceptableNot AcceptableNot AcceptableNot Acceptable AcceptableAcceptableAcceptableAcceptable

PVA Paint Epoxy or Enamel paint

Window sills Flush glazed windows

Exposed pipes Smooth surfaces

Horizontal pipes & services Concealed services

Open floor drains Hygienic drains

Horizontal pipes & services Concealed services

Open floor drains Hygienic drains

Floor cracks, flaking floor surfaces

Homogonous sealed floors –epoxy finish or welded vinyl

Ceiling cracks & joints Smooth sealed ceilings

Exposed, open light fittings Flush light fittings

Wooden furniture S/Steel furniture

HEATING, VENTILATION AND AIRHEATING, VENTILATION AND AIRHEATING, VENTILATION AND AIRHEATING, VENTILATION AND AIR----CONDITIONING (HVAC) SYSTEMCONDITIONING (HVAC) SYSTEMCONDITIONING (HVAC) SYSTEMCONDITIONING (HVAC) SYSTEM

� Humidity, temperature, pressurization and air filtration or air cleanlinessshall be controlled in order to protect the products, personnel and theenvironment.

� Due consideration shall be given to the placement of ceiling mounted HEPAfilters to avoid creating of air currents inside the cabinet underneath.Diffusers shall not be used

� Pre-filters (primary and secondary) of AHU and HEPA filters shall bechangeable from outside the clean roomchangeable from outside the clean room

� Equipment installed shall not jeopardise the set room conditions includingtemperature, humidity, air pressure, noise level, etc

� Air return grilles shall be located at a low-level to sweep or purge the rooms

� Air extracted from areas where cytotoxic drugs are reconstituted shall not bere-circulated; air outlets shall be designed to avoid possible environmentalcontamination from particles and vapors

50

CRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERSCRITICAL PARAMETERS

51

CLEANROOM CRITICAL PARAMETERCLEANROOM CRITICAL PARAMETERCLEANROOM CRITICAL PARAMETERCLEANROOM CRITICAL PARAMETER

�Particle count�Microbial load�Differential pressure�Airflow pattern

Air change rate�Airflow pattern�Air change rate�Temperature�Relative humidity

AIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATION

At RestAt RestAt RestAt Rest In OperationIn OperationIn OperationIn Operation

GradeGradeGradeGrade

Max Permitted no. of particles per m3

0.5 um 5um 0.5um 5um

AAAA 3520 20 3520 20

BBBB 3520 29 352 000 2 900

CCCC 352 000 2 900 3 520 000 29 000

DDDD 3 520 000 29 000 Not Defined Not Defined

PIC/S GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL

PRODUCTS IN HEALTHCARE ESTABLISHMENTS; PE 010-3;1ST October 2008

AIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATIONAIRBORNE PARTICULATE CLASSIFICATION

• Classification of clean rooms are as followed:

PIC/SPIC/SPIC/SPIC/S ISOISOISOISO USUSUSUS Fed Standard Fed Standard Fed Standard Fed Standard

209D209D209D209D

GradeGradeGradeGrade AAAA ISO Class 5 Class 100

Grade BGrade BGrade BGrade B ISO Class 6 Class 100

Clean

Grade BGrade BGrade BGrade B ISO Class 6 Class 100

Grade CGrade CGrade CGrade C ISO Class 7 Class 10 000

GradeGradeGradeGrade DDDD ISO Class 8 Class 100 000Less Clean

MICROBIAL MONITORINGMICROBIAL MONITORINGMICROBIAL MONITORINGMICROBIAL MONITORING

GradeGradeGradeGrade

RecommendedRecommendedRecommendedRecommended limits for microbial contaminationlimits for microbial contaminationlimits for microbial contaminationlimits for microbial contamination

Air sample

(cfu/m3)

Settle Plates

cfu/4hr(dia 55 mm)

Contact

Plates

cfu/plate(dia 90 mm)

Glove print 5

fingers

(cfu/glove)(dia 90 mm)

AAAA <1 <1 <1 <1

BBBB 10 5 5 5

CCCC 100 50 25 -

DDDD 200 200 50 -

PIC/S GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL

PRODUCTS IN HEALTHCARE ESTABLISHMENTS; PE 010-3;1ST October 2008)

DIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSURE• Pressure differential gradients is used to prevent cross-contamination

• Require “cascading” from high (clean) to lower grade (less clean)

• Pathogenic, highly toxic, radioactive materials the pressure cascade may bedifferent

• Adjacent rooms to have pressure difference of 10 – 15 pascal (1.0 – 1.5 mmHg)

Grade A

Grade B

Grade C

Grade D

+ + + +

+ + +

+ +

+

0 Pa

DIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSURE

25 Pa

20 Pa

20 Pa

15 Pa

TPNTPNTPNTPN

15 Pa

DIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSUREDIFFERENTIAL PRESSURE

15 Pa

20 Pa

15 Pa

CDRCDRCDRCDR

30 Pa

15 Pa

15 Pa

AIR CHANGE RATEAIR CHANGE RATEAIR CHANGE RATEAIR CHANGE RATE

• Amount of air cycled in room per hours

• Performance depend on design of AHU system

• For flushing of particulate matters from air

• To attain good air flow pattern and pressure differentials

• The limits of the ACR taken from Australian Standard AS 1807.3-2000 are as follows:2000 are as follows:

� Grade A : > 120 / hour

� Grade B : > 40 / hour

� Grade C : > 20 / hour

� Grade D : > 20 / hour

AIR FLOW PATTERNAIR FLOW PATTERNAIR FLOW PATTERNAIR FLOW PATTERN

• Air velocity from HEPA tobe 0.45 m/s+ 20%

(vertical = 0.30 m/s+ 20%)

• Grade B clean room is anon-unidirectionalGrade B clean room is anon-unidirectionalairflow room but aspect toobserve some degree ofsweeping effect

TEMPERATURETEMPERATURETEMPERATURETEMPERATURE

• Temperature comes from the degree of intensity of heat ofatmosphere

• An important parameter to be considered in preparation of heat-sensitive product or heat-sensitive equipments

• Usually it is aim for personnel comfort

• Specification of temperature?

Depends on nature of product to be prepared. Although mostspecification depends on the products and equipment, but most aretargeted at personnel comfort (eg. Not more than 22 °C). This specsfavor all range of products.

RELATIVE HUMIDITY (% RH)RELATIVE HUMIDITY (% RH)RELATIVE HUMIDITY (% RH)RELATIVE HUMIDITY (% RH)

• What is relative humidity?

The ratio of the amount of water vapor in the air at a specifictemperature to the maximum amount that the air could hold at thattemperature, express as a percentage

• Specifications of relative humidity?

Same as temperature, it depends on the nature of product to beprepared.prepared.

• It is important to know that low RH, reduces the risk of microbial proliferation. These are the example of common level of humidity applied in different product preparation:

� Normal Product : 50 – 65 % RH

� Dry Product : 40 – 50 % RH

� Humidity sensitive-product : < 15 % RH

REFERENCESREFERENCESREFERENCESREFERENCES� PIC/S Guide To Good Practices For The Preparation Of

Medicinal Products In Healthcare Establishments. PE 010-3.1st October 08.

� PIC/S Guide To Good Manufacturing Practice For MedicinalProducts. PE 009-09, 1st September 2009.

� Guidelines On Good Manufacturing Practices For

63

� Guidelines On Good Manufacturing Practices ForPharmaceuticals Products, Who Expert Committee OnSpecifications For Pharmaceutical Preparations, 2003.

� The Quality Assurance Of Aseptic Preparation Services; TheNHS QC Committee, June 2000.

� Guides to the Development of Sterile PharmaceuticalPreparation Facilities for Healthcare Establishments; 1st

Edition; March 2010

THANK YOUTHANK YOUTHANK YOUTHANK YOU

64