SARANA PENUNJANG

KRITIS INDUSTRI FARMASI

SARANA PENUNJANG KRITIS
1. HVAC (Heating,Ventilation and Air Conditioning)
2. Water System
3. Compressed Air
 SISTEM TATA UDARA
FAKTOR LINGKUNGAN
BERDAMPAK LANGSUNG TERHADAP KUALITAS PRODUK

• Cahaya
Suhu
Kelembaban (RH)
Kontaminasi mikroba
Kontaminasi partikel
Kontaminasi silang
 SISTEM TATA UDARA

KRITERIA UNTUK MENENTUKAN SISTEM TATA UDARA

YANG EFEKTIF :
▪ Struktur dan konstruksi akhir (‘finishing’) bangunan
▪ Penyaringan udara
▪ Kecepatan pertukaran udara (‘air change’)
kecepatan pembuangan udara ‘kotor’
▪ Arah alir udara lokasi pembuangan udara
▪ Tekanan udara dalam ruangan
▪ Temperatur
▪ Kelembaban (‘Humidity’)
 Skematika Sistem HVAC

Silencer Flow rate controller Fan Filter

Weather louvre Control damper Single pass

+
Primary Humidifier
Filter Fine filter

Cooling register Secondary

Production Room
with Filter
droplet
separator Exhaust
Heating
register
Resirkulasi
 SISTEM TATA UDARA
(WHO,TRS 937,2006)
AIR HANDLING UNIT
F = FRESH AIR

SECONDARY
COOLING COIL
R = RETURN AIR

AIR FAN
PRIMARY

SUPPLY

FILTER
FILTER

S = SUPPLY AIR

RE-HEATER

R S S S HEPA
FILTER

PROD. ROOM R R R R
WITH
HORIZONTAL 0,3m/ s PROD. ROOM
WITH LOW LEVEL
HEPA FILTERS

LAM. FLOW
PRODUCTION ROOM RETURN
WITH VERTICAL
LAMINAR FLOW

0,45m/ s

ROOM A ROOM B ROOM C

Horizontal laminar flow Vertical laminar flow Turbulent flow

Posisi Grill Udara Balik
 DISTRIBUSI UDARA

TURBULENT AIR FLOW UNI-DIRECTIONAL /

LAMINAR AIR FLOW

33
 Parameter Kritikal HVAC

• Jumlah partikel di udara lingkungan

• Jumlah mikroba di udara lingkungan dan pada
permukaan obyek
• Jumlah pergantian udara
• Kecepatan aliran udara, pola aliran udara
• Filter (jenis, posisi)
• Perbedaan tekanan udara antar ruangan (pressure
differential)
• Temperatur
• Kelembaban (RH)
 Klasifikasi Partikel Udara
Kelas At rest (non operasional) Operasional

Jumlah maksimum partikel/m3 yang diperbolehkan

untuk kelas setara atau lebih tinggi
≥ 0,5 µm ≥ 5 µm ≥ 0,5 µm ≥ 5 µm

A 20 3.520 20
3.520
B 29 352.000 2.900
3.520
C 2.900 3.520.000 29.000
352.000
D 3.520.000 29.000 Tidak Tidak
ditetapkan ditetapkan
E 3.520.000 29.000 Tidak Tidak
ditetapkan ditetapkan
 Batas yang disarankan untuk Cemaran
Mikroorganisme Ruang Bersih (nilai rata-rata)
Batas Cemaran Mikroorganisme (nilai rata-rata)

Kelas Air sample Settle plate Contact plates Glove print 5

(cfu/m3) (dia.90 mm) (dia.55 mm) fingers
cfu/4 jam *) cfu/plate cfu/gloves
A <1 <1 <1 <1

B 10 5 5 5

C 100 50 25 -

D 200 100 50 -

*) Dapat dipaparkan kurang dari 4 jam

SISTEM TATA UDARA

Kls Higiene A / B (I)

Kls Higiene C (II)

Risiko terapetik
Kls Higiene D (III)
Lain-lain
Lain-lain
Kls IV
Ketentuan Lingkungan
 Room Class Required Is Dependant on
Manufacturing Process Being Carried Out !

R uang kelas
Manufacturing Environment

Ruang Kelas E
requirements

Ruang Kelas
F - Pencampuran,
G - Pengolahan.
Pengemasan - Pengisian,
- Gudang Sekunder - Pengemasan
- Laboratorium Primer
- Kantin
- Workshop

Therapeutic risks
Definisi Status HVAC Ruangan

as built at rest In operation

air air air

Desain Statik Dinamik

WATER PURIFICATION SYSTEM
(SISTEM PENGOLAHAN AIR)
 DESIGN PHILOSOPHIES
• Pharmaceutical water is the most widely used ingredient
in drug manufacturing and the main component in
equipment/system cleaning.
• Control of chemical and microbiological quality is
important
• It must be demonstrate that all pharmaceutical water can
be produced consistently to specification
 DESIGN PHILOSOPHIES

♦ Specification of pharmaceutical water quality:

Pharm.water uses can be categorized as :
a. Ingredients in a dosage form manufacturing process,
b. Ingredient in an API process,
c. Equipment cleaning or rinsing
♦ Critical process parameter :
Parameters, which directly affect the water quality at ,or after, a
treatment step
 DESIGN PHILOSOPHIES

♦ cGMP compliance issues,f.i :

a. Continuous,turbulent flow
b. Elevated or reduced temperature
c. Smooth,clean surfaces
d. Flood distribution loop
e. etc
 Types of water used in
pharmaceutical processes
• Purified water
• Water for Injection
• Pure, or clean steam
 USP Purified Water
• Is obtained from water complying with U.S.
- Environmental Protection Agency (EPA),
- National Primary Drinking Water Regulations (NPDWR),
- or comparable regulations of the European Union or Japan,
- and will be referred to subsequently as Drinking water.
• Contain no added substance
• Is obtained by a suitable process
• Meets the requirements for water Conductivity
• Meets the requirements for TOC
 Purified Water (PW)
(USP)
• It is used for as excipient in the production of :
a.Nonparenteral preparations, and
b.Other pharmaceutical applications
(cleaning/rinsing, tests and assays)
• Produced by suitable process.
• Minimum quality of water sources (feed water) :
same quality as drinking water
( US-EPA/EU/Japan/WHO)
• Purification of water sources : by unit operations
that could include deionisation, distillation, ion
excange, RO, EDI, filtration, UV light
 Purified Water (PW)
(USP)
• Must meet the requirements for ionic and
organic chemical purity.
• Must be protected from microbial
contamination
• Contain no added substances
 Purified Water
Quality Requirements (FI VI/USP)
• Conductivity : < 1,3 μS/cm at 25°C*
• Total Organic Carbon (TOC) : < 0.5 ppm
• Aerobic Microbial Contamination : < 100 CFU/ mL
• Endotoxin content : not Specified

Note :
All Pharmaceutical water must also meet the EPA standard for
microbiological quality of potable water
.
*In-line
measurement, from equivalent values from USP table
CFU=Colony Forming Units
 Water For Injection (WFI)

Is is used as :
▲ an exipient in the production of parenteral
dosage forms
▲ other preparations where product endotoxin
content must be controlled,
▲ Cleaning (rinsing) of certain equipment and
parenteral products-contact component.
 Water For Injection (WFI)

• Minimum quality of feed water sources : meets

the requirements of Pure Water
• Production of WFI : By distillation/superior
process for removing chemicals and
microorganism
• Must meet the requirements for ionic and
organic chemical purity.
• Must be protected from microbial contamination
• Contain no added substances
 Water for Injection
Quality Requirements (FI VI/USP)
• Conductivity :< 1,3 μS /cm at 25°C
• Total Organic Carbon (TOC) : < 0.5 ppm
• Aerobic Microbial Contamination : < 10 CFU/100 mL
(< 0.1 CFU/mL)
• Endotoxin content : < 0.25 EU/mL
Note :
All Pharmaceutical water must also meet the EPA standard
for microbiological quality of potable water
 SOURCE OF RAW WATER
1. Rain water
2. Surface or ground water
3. Well or borehole
4. Municipal or civil – “tap water”
5. Purchased in bulk

It must be purified
 Treatment Guidance
• The following should be monitored :
– Sources of water
– Treatment Procedures
– Water Treatment Equipment
– Treated water tests
– Monitoring records required
 PRE-TREATMENT DIAGRAM

Suspended
Suspended Membrane
Microbial
Solids
Solids Chlorine Scale
Control
Removal
Removal Removal Inhibitor

•Multi Media Filter •Activated Carbon •Water Softener •Ultraviolet

•Cartridges Filter •Chemical Injection •Chemical Injection •Chlorine
•Ozone

A final Treatment system WILL NOT operate reliably over the long
term, without reliable operation of the pre-treatment system
Reliable Operation and control of pre-treatment can significantly
reduce operating and maintenance cost in final treatment
 Water pre-treament (example)

Raw water
Sand filter Fe-Mn Filter
storage tank

Carbon Tap water

Filter tank Distribution
 Water Treatment Diagram (example)

Raw Raw Water Tap Water

Water Tap water
Water storage
pre-treatment
storage
source tank tank

Soft water Filter Reverse Filter

Softener storage (10µm) Osmosis ( 0,2 µm)
tank

WFI
PW tank Distiller Storage
tank

Distribution Distribution
Selection of Water for Pharmaceutical Purposes (USP)
 Materials that come into contact with
systems for WPU (WHO)
• Includes : Pipe work, valves and fittings, seals,
diaphragms and instruments, should be selected
to satisfy the following objectives.
► Compatibility : All materials used should be
compatible with the temperature and chemicals used by
or in the system.
► Prevention of leaching: All materials should be non-
leaching at the range of working temperatures.
► Corrosion resistance : PW, HPW and WFI are highly
corrosive. All materials should be corrosion resistance.
 Materials that come into contact with
systems for WPU

► Smooth internal finish :Smooth internal surfaces help

to avoid roughness and crevices within the WPU system.
Crevices are frequently sites where corrosion can
commence.
► Jointing : The selected system materials should be
able to be easily by welding in a controlled manner.
► Design of flanges or unions : Where flanges or
unions are used, they should be of a hygienic or sanitary
design
Materials that come into contact with
systems for WPU

► Documentation : All system components should be

fully documented and be supported by original or
certified copies of material certificates.
► Materials : Suitable materials that may be considered
for sanitary elements of the system include 316 L (low
carbon) stainless steel, polypropylene,
polyvinylidenedifluoride and perfluoroalkoxy
(WHO, Technical Report Series 929/2005)
 SYSTEM DESIGN
• Type of products to be manufactured
• Pipes sloped so water does not pool and can be
drain easily
• Sanitary fittings & Connections
• Constructed of suitable materials
• Temperature of the systems
• Circulating or one way system ( a one way
systems is basically “dead leg”)
• Level of Quality that is desired
 SYSTEM DESIGN
• Incorporate non return valves
• Purified water systems require frequent
sanitization and microbiological monitoring
to ensure water of appropriate
microbiological quality at the point of use.
 PIPE SYSTEM DESIGN

Flow direction arrows

on pipes are important

Deadleg section

X <2D
If D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.

Sanitary Valve
Water scours deadleg

There should be no dead legs

 Biofilm
A biofilm is defined as bacterial cells adherent to each
other and/or to surfaces or interfaces and are covered
by a slimy substance, which acts as a shield, protecting
the biofilm from physical and chemical attack.

Ref: Biofilms – Survival and growth of bacteria in compendial high purity water systems by Frank Riedewald and Aidan W. Sexton:
Pharmaceutical engineering Vol.27 No 1.
Bio-film formation
1. Free swimming aquatic bacteria use
polymucosaccharides to colonise surfaces
2. Complex communities evolve which shed
micro-colonies and bacteria
 Water purification & distribution loop
Purification process
Distillation system

Reverse Electro-
Feed osmosis deionisation Tank
water

Tank

Distribution loop
 Hot Storage, Hot Distribution
Control Valve
(optional)

Steam
Hot
Storage
Tank

Cond.
Most Advantageous When:
•Hot water is required
•Hot water is generated
•Microbial control is critical
Least Advantageous When:
•Ambient temperature water
required
 Hot Storage, Cool & Reheat
Control Valve Steam
(optional)

T
Reheat Exchanger
Cond.
Steam
Hot
Storage Coolant
Tank

T
Cooling Heat
Exchanger
Cond. Coolant

Most Advantageous When:

•Water is generated hot
•Tight microbial control is required
•There is little time for sanitization Least Advantageous When:
•Water consumption is critical (no flushing) •Energy consumption is critical
 Typical water storage and distribution schematic
Hydrophobic air filter
Feed Water & burst disc
from
EDI or RO
Cartridge
filter 0.2 µm
Spray ball

Water Optional
in-line filter
must be 0,2 µm

kept
circulating
UV light
Outlets

Heat Exchanger
Air break
Ozone Generator Hygienic pump
to drain
 How to validate a water treatment system (USP)
• Defines the critical process parameters and their
operating ranges.
• A validation programs the design, installation, operation
and performance of equipment.
• Stages :
- Qualification of the installation (IQ),
- Operational Qualification (OQ),
- Performance Qualification (PQ)
• Validation
Validation of Water System

• Consists of three phases :

• Phase 1 : 2-4 weeks (14-28 days)
• Phase 2 : 2- 4 weeks (14-28 days)
• Phase 3 : 1 year
Phase 1: Investational Phase (2 – 4 weeks)

• DQ, IQ and OQ
• Develop
– operational parameters
– cleaning and sanitization procedures and
frequencies
• Sample daily at each point of use
• End of Phase I, develop SOPs for the water
system
 Phase 2 : verifying control (2-4 weeks)

• Demonstrate the system is in control

• Same sampling as in phase 1
• The water can be used for routine production
Phase 3 : verifying long-term control (1 year)

• PQ
• Demonstrate the system in control over a long
period of time
• Weekly sampling
RO dan EDI Unit
 Studi Kasus
• Departemen QC melaporkan bahwa hasil
pemeriksaan cemaran mikrobiologi air murni
( Purified Water) yang diambil sampelnya di
ruang granulasi pada tanggal 21 Desember
2020 adalah 150 cfu/mL.
• Tindakan apakah yang harus dilakukan oleh
industri tersebut ?
• Hal-hal apakah yang dapat menyebabkan
meningkatnya cemaran mikroorganisme tsb?
 References
1. USP 42-NF 37 (2019).
2. FI VI (2020)
2. WHO-TRS 970 Annex 2,WHO GMP : Water For
Pharmaceutical Use 2012
3. ISPE Baseline Guide,Vol.4 : Water and Steam System,
2nd ed.(2011)
4. BPOM RI ,Petunjuk Teknis Sarana Penunjang Kritis
Industri Farmasi (2013)