ELPHARMA MULTI SOLUTION

CONTENT OF TOPICS

1 Introduction of Sterile Process

• Terminal Sterilization & Aseptic Processing

2 Types of Sterile Dosage Form

3 Flow of Sterile Production Process

4 Major Equipments Used in Sterile Production

5 Understanding Aseptic Behaviour

 1 Introduction of Sterile Process

STERILE DOSAGE FORM

Sterile dosage form is a product introduced in a manner that circumvents the body’s most protective
barriers, the skin and mucous membranes, and, therefore, must be “essentially free” of biological
contamination.

A sterile dosage form is absolutely free of any form of biological contamination.

 1 Introduction of Sterile Process
TERMINAL STERILIZATION vs ASEPTIC PROCESSING
• Aseptic process
HOW IT IS PROCESSED?
• Terminal Sterilization

• Small volume ( 10 - 100 ml)

VOLUME OF DOSAGE FORM
• Large Volume (> 100 ml)

• Dry injection
TYPE OF DOSAGE FORM • Liquid Injection
• Lyophillized Injection
• Emulsion / Suspension
 Sterile Process Production
Products that can be sterilised in their final container are
“Terminally sterilized products”

Products that cannot be sterilised in their final container are

“Aseptically manufactured products”

HOW
TO
DECIDE?
 1 Introduction of Sterile Process
TERMINAL STERILIZATION
vs
ASEPTIC PROCESSING
HOW
TO
DECIDE?

F0 value is the time in minute for the specified temperature

that gives the same thermal lethality as at 121 C in one minute.

EMEA Guideline, Decision tree For The Selection of

Sterilization Method (CPMP/QWP/054/98)
2 Types of Sterile Dosage Form

•Conventional Small
Volume Injectables

•Conventional Large
Volume Injectables
2 Types of Sterile Dosage Form
• Conventional Small Volume Injectables

SOLUTIONS SUSPENSIONS SOLIDS EMULSIONS

Ready-to-use Suspensions can be coarse (macro) or Solids injectable Emulsions are also
products or can micronized (micro- or nanosuspension) are usually in dispersed systems
lyophilized combining an oil
be liquid solids dispersed in a suitable vehicle, either products and phase with an
concentrates water or oil. powder aqueous phase
(aqueous only) products. More
Insulin, vaccines, and microsphere delivery
subsequently stable in solid
systems are formulated and delivered as phase.
diluted in a
injectable suspensions.
smaller container
or within a Suspensions, unless the dispersed particles
suitable IV fluid are nanoparticles, can not be administered
by the IV route.
2 Types of Sterile Dosage Form
• Conventional Small Volume Injectables

EXAMPLES:
(A) Solution
Source: Courtesy of Baxter Healthcare Corporation.
(B) Suspension
Source: Courtesy of Dr. Gregory Sacha, Baxter.
(C) Lyophilized Powder
Source: Courtesy of Eli Lilly and Company.
(D) Emulsion
Source: Courtesy of Teva Pharmaceuticals
2 Types of Sterile Dosage Form
• Conventional Small Volume Injectables
TYPICAL EMULTION FORMULATIONS
(A)Large volume — typical formulation — soybean
oil (10–20%) (linoleic, oleic, palmitic oils; unsaturated
fatty acid triglycerides), egg yolk phospholipid (1.2%),
glycerine (2.5%),Water for Injection.
Source: Courtesy of Baxter Healthcare Corporation.

(B)Smallvolume — typical formulation — soybean

oil, egg lecithin, glycerin, Water for Injection, Ph
approximately 8.0—for example, Propofol R, Vitalipid R,
Limethason R, Lipfen R, Liple R, Diazemuls R, Fluosol R
Source: Courtesy of Teva Pharmaceuticals.
2 Types of Sterile Dosage Form
• Conventional Small Volume Injectables
Solids
 Solids are prepared primarily by lyophilization after liquid filling with secondary
preparation by sterile crystallization and powder filling.
 The reason most sterile solids are prepared by lyophilization is the fact that liquid filling
presents less problems than powder filling and for powder filling the product needs to be
crystalline in solid state character.
 Most injectable cephalosporins, because they can be crystallized, are filled
as sterile powders.
 Another category of solids are the solid implants, surgically inserted within bodily tissue,
primarily for prolonged action pharmaceuticals.
2 Types of Sterile Dosage Form
• Conventional Large Volume Injectables

Electrolyte Carbohydrate Nutritional

Solutions Solutions Proteins

Fatty (Lipid) Peritoneal Irrigating

Emulsions Dialysis Solutions
2 Types of Sterile Dosage Form
• Main Categories For Injectable Products
Solutions, ready for injection
Dry, soluble products ready
to be combined with a
solvent prior to use
Suspensions, ready for
injection
Dry, insoluble products
ready to be combined with a
vehicle prior to use
Emulsions
Liquid concentrates ready
for dilution prior to
administration
3 Flow of Sterile Production Process

TYPICAL ASEPTIC
PRODUCT HANDLING
PROCESS
 3

Stoppering
ASEPTIC FILLING LINE Crimping
EXAMPLE
Filling Needle

Sealed Vials
Sterile Vials
 There are various filling line designs by which aseptic filling can be
accomplished. The different designs will provide different levels of
microbial protection:

Conventional Aseptic Filling (Most Common)

ASEPTIC FILLING better

Restricted Access Barrier Systems (RABS)

best

Isolators
ASEPTIC FILLING: Conventional Aseptic Processing
Conventional Aseptic Processing is accepted for current filling process

Consists of a Grade A environment over the filling process with grade

B background

Generally there is a soft or hard wall separation between the

operator and critical areas

The non-product contact parts are manually sanitized

Operators will routinely enter critical area for interventions

Example : Laminar Air Flow (LAF)

ASEPTIC FILLING: Conventional Aseptic Processing
ASEPTIC FILLING: Restricted Aseptic Barrier Systems (RABS)
RABS are designed to prevent operators from entering into
critical zones (Grade A)

Generally there is a hard wall separation between the

operator and critical areas

Interventions are done “primarily” via glove ports/half suits

Consists of a Grade A environment over the filling process

contained within a Grade B background

Minimum requirement for new installation or major

upgrade

Sanitization usually includes a higher level of disinfection

ASEPTIC FILLING: Isolators

Isolators are increasingly being expected by regulatory agencies

The interior of an isolator is Grade A with positive air to the

outside but the background air classification can be either Grade C
or Grade D

Interventions are done “only” via glove ports/half suits and are
designed to prevent operators from entering into critical zones

Isolators require entry/exit ports for sterile material transfers from

the outside to the inside

Material transfers are critical to the process to prevent

contamination and serve to protect the interior environment of the
isolator
FLOW OF MATERIAL & PERSONNEL

• Flow of Material and Personnel in Pharmaceutical manufacturing

should be designed to minimize product and process contamination.
• Material flow is generally unidirectional, with the flow moving from less
clean areas to cleaner ones
• Personnel gown and de-gown in separate rooms and airlocks are
used to segregated different air qualities within a room
• Personnel must not introduce contaminant into the product as they
move from one area to another
• Should consider flow of waste material. Waste should be removed from
the facility without contaminating the product using one way pass
through
• For personnel flow, items such as step over benches, door interlocks, or
time delays are used to segregate different clean areas and to prevent
reduce pressure gradients and two way access into controlled areas
3 Flow of Sterile Production Process
 Manufacturing Process of
LIQUID INJECTION (Aseptic Process)

Filtration
Filtration with
Sterile filter

Raw Dispensing Preparation

Material API & Dissolve API
Excipients & Excipients

Vial Washing Sterilization Filling Capping Visual

Automatic Vial Vial Sterilization by Filling to vial or Cap sealing Inspection
washing process Dry Heat ampoule

MANUFACTURING PROCESS
Flow Chart of Production Process of vial Injection Finished Medicines(Liquid)
 Manufacturing Process of
LYOPHILIZED INJECTION (Aseptic Process)

Filtration
Filtration with
Freeze Drying
Sterile filter Liquid filled vial sublimate
by freeze dryer

Raw Dispensing Preparation

Material API & Dissolve API
Excipients & Excipients Loading Unloading
Fully Automated Loading
Unloading

Vial Washing Sterilization Filling Capping Visual

Automatic Vial Vial Sterilization by Filling to vial or Cap sealing Inspection
washing process Dry Heat ampoule

MANUFACTURING PROCESS
Flow Chart of Production Process of vial Injection Finished Medicines(Freeze Dry)
 Containment System For Oncology Injectable
Conventional Aseptic Process Vs. Containment Aseptic Process

Sterile Filtration Conventional Single Use Bag closed RABS

C- RABS

Mixing Tank Sterile Filter LAF Mixing Tank Single Use Bag
with Filter
Filling
Machine
Filling
Machine

Opened

Sterile Filtration with 0.2 ㎛ Filter Opened and partially covered Filtration and handle with Singe Use bag Fully Cover and seal Whole Filling Line
Standard Level Contamination Need to open during filling No Bacteria & Particle Contamination No need to Open during Filling
protection for ‘ Bacteria & Particle Moderate Level Contamination No Contamination (Bacteria, Particle)
Need to clean and re-use. No Safety protection for Operator No Cross Contamination (single use). High Safety Protection for Operator
4 Major Equipment Used in Sterile
Production
STERILE PRODUCTION
EQUIPMENTS
4 Major Equipment Used in Sterile
Production
DISPENSING
Laminar Air Flow Biosafety Cabinet Dispensing Isolator
4 Major Equipment Used in Sterile
Production
COMPOUNDING
Mixing Facility Mixing Facility Under Isolator

Stainless 316L, surface roughnes Ra 0,1-0,8 micron,

cleaning in place, sterilization in place
4 Major Equipment Used in Sterile
Production
TRANSFER & FILTRATION
Filter Capsule
Filter Skid

Integritry Filter Test

Filter
Cartridge
 4 Major Equipment Used in Sterile
Production
INLINE FILLING MACHINE (Washing, Sterilization /
Depyrogenation, Filling, Closing Filter Capsule

CRABS

https://ferrygrp.com/representations/steriline-srl/

https://ferrygrp.com/representations/steriline-srl/ ISOLATOR
4 Major Equipment Used in Sterile
Production
INLINE FILLING MACHINE (Washing, Sterilization /
Depyrogenation, Filling, Closing Filter Capsule

Capping
Machinge

https://ferrygrp.com/representations/steriline-srl/
4 Major Equipment Used in Sterile
Production
INLINE FILLING MACHINE (Washing, Sterilization / Depyrogenation,
Filling, Closing
Freeze
Dryer

https://ima.it/pharma/machine/lyofast/
4 Major Equipment Used in Sterile
Production
INLINE FILLING MACHINE (Washing, Sterilization / Depyrogenation,
Filling, Closing
Ampoule
Filling
4 Major Equipment Used in Sterile
Production
INLINE FILLING MACHINE (Washing, Sterilization / Depyrogenation,
Filling, Closing

Form Fill Seal for

Soft Bag
4 Major Equipment Used in Sterile
Production
Depyrogenation
STERILIZATION & DEPYROGENATION Oven

Superheated
Water Autoclave

Steam
Autoclave
Depyrogenation
Oven Tunnel
 4 Major Equipment Used in Sterile
Production
ROOM BIO DECONTAMINATION / STERILIZATION

Automatic Dry
Fog Machine
Dry Fog
Sterilization

Hidrogen Peroxyde
Vapour Generator
 4 Major Equipment Used in Sterile
Production Automatic Visual
VISUAL INSPECTION Semi Auto Visual Inspection Machine
Inspection Machine

Manual Visual
Inspection Table
 5 Aseptic Behaviour in Cleanrooms

Aseptic technique is a set of specific practices and

procedures performed under carefully controlled
conditions with the goal of minimizing contamination.

Aseptic Technique Aseptic Practice Aseptic Behavior

5 Aseptic Behaviour in Cleanrooms
WHY IT IS NEEDED?

Source

Of Contamination

PEER
5 Aseptic Behaviour in Cleanrooms
WHY IT IS NEEDED?
Cont’d
5 Aseptic Behaviour Does not bring
or wear any of
the Prohibited Follow
in Cleanrooms Appropiate
Cleaning and
Desinfection
things into the
Clean Room
Communication
Behaviour

Maintain
Access Gowning &
ControlAnd Gloves
Personnel
Movement Aseptic Integrity

Technique
Equipment, And Follow
Material are
used, stored, Behaviour Proper
Gloves
HOW TO ACHIEVE and
transferred Sanitization
properly
GOALS? Ensure Follow
Enviromental Appropriate
sampling Ensure Body
appropriately Presure Movement
Taken Differential
maintained
well
5 Aseptic Behaviour
in Cleanrooms
EXAMPLE… √
OR

Do you know how to stand

correctly in the aseptic area?
X
5 Aseptic Behaviour
in Cleanrooms
EXAMPLE…
How do we move in the
aseptic processing area..??

X OR
√
 5 Aseptic Behaviour
in Cleanrooms
EXAMPLE…

Aseptic items must not be If items dropped on the floor,

Workareas must be clean,
placed on the floor, or any it must NOT be picked up
neat and tidy
other un-sanitised surface during a critical activities

Use of disinfectant sprays Increase in activity/personnel

In the cleanrooms should
should be spray away from = increased chance of
define maximum numbers of
particle counters (avoid contaminating
personnel
excessive particles) product/facility
5 Aseptic Behaviour in Cleanrooms
Real Example! (Hand Washing /
Glove Sanitization)

FAILED
TO
COMPLY
 CONTACT
INFORMATION
0812 - 1602 - 6828
0813 - 4555 – 6227

elpharmamultisolution@gmail.com

@elpharma_multisolution

Elpharma Multi Solution

9/25/2021 PT KUSUMA PERSADA ENGINEERING 48