Aseptic Manufacturing

By:
Dr Mehdi Rajabi
 My talk’s layout
◼ Introduction
◼ Aseptic manufacturing overview
◼ Definition
◼ Sources of product contamination
◼ Principle
◼ Design of aseptic units
◼ Isolator technology and types
◼ Premises
◼ Quality management
◼ QA, GMP and QC
◼ References
 Introduction
◼ From early 1900s, the first parenteral drugs were
manufactured
◼ need arose to find suitable sterilisation methods for
heat sensitive products
◼ Drugs should be sterile without any final sterilisation
technique
◼ standards for AM- vital & clearly specified
◼ Standards- manufacturing room, the personnel, the
equipment and the supply systems
 Aseptic manufacturing overview
What happens in AMU?
Quality Control &
Aseptic process &
Quality Assurance
(QC, QA) Technique

Cytotoxic
Drugs

Standard Operating
Procedure (SOP) Central IV
Aseptic
Additive
Manufacturing
Services
Unit (CIVAS)

Total
Good Parenteral
Manufacturing Nutrition
Practice (GMP) (TPN)
Training &
 Definition
◼ Aseptic Technique
◼ The technique for manipulation of compounded
sterile products and parenteral preparations that
prevents contamination
◼ Contamination- any effect or action that has a
negative impact on a product’s integrity making it
unfit for use
◼ Chemical composition
◼ PH
◼ Sterility
◼ Biological or therapeutic potency
◼ Physical appearance
Sources of product contamination
◼ People (most common)
◼ Touch contamination
◼ Generation of particulates from shedding cells or hairs
◼ Supply air
◼ Heating ventilation and air conditioning (HVAC)
◼ Infiltration
◼ Particles from adjacent spaces (e.g. anteroom)
◼ Internal generation
◼ Walls, floors, ceilings, packaging and equipments
 Principle
◼ The manufacturer of sterile products is subject to
special requirements in order to minimise risks of
microbiological contamination, and of particulate and
pyrogen contamination
◼ Much depends on the skill, training and attitude of the
personnel involved
◼ Quality assurance is particularly important, and this
type of manufacture must strictly follow carefully
established and validated methods of preparation and
procedure
◼ Sole reliance for sterility or other quality aspects must
not be placed on any terminal process or finished
product test
 Design of aseptic units

◼ Manufacture of sterile products should be carried out in

clean areas- entry which should be through airlocks for
personnel and/or for equipment and materials
◼ Clean areas should be maintained to appropriate
cleanliness standard and supplied with air which has
passed through filters of an appropriate efficiency
◼ Various operations of component preparation, product
preparation and fillings should be carried out in separate
areas within the clean area
◼ Manufacturing operations are divided into categories: first
those where the product is terminally sterilised, secondly
those which are conducted aseptically at some or all
stages
Pictures of Clean room
 Design of aseptic unit Cont.

◼ For aseptic manufacturing monitoring should be

frequent using methods such as settle plates,
volumetric air and surface sampling (e.g. Swabs and
contact plates)
◼ Results from monitoring should be considered when
reviewing batch documentation for finished product
release
◼ Surface and personnel should be monitored after
critical operations
◼ Additional microbiological monitoring is also
required outside production operations (e.g. After
validation of system, cleaning and sanitisation
 Design of aseptic unit Cont.
Grade Air sample Settle plate Contact plates Glove print
(cfu/m3) (diam. 90mm) (diam. 50mm) Cfu/glove
cfu/4hrs cfu/plate
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -

Recommended limits for microbial contamination

◼ Appropriate alert and action limits should be set for
the results of particulate and microbiological
monitoring-if limits exceed operating procedures
should prescribe corrective action
 Isolator technology
◼ The utilisation- minimise human intervention
◼ There are various type of isolators and transfer
devices
◼ Isolators are constructed of various materials
◼ Transfer device can be single/double door- potential
of contamination
◼ HEPA filters- used to clean air entering rooms and
remove all airborne particles 0.3mm or larger with an
efficiency of 99.97%
◼ Operations for aseptic preparations:
◼ Grade A- Aseptic preparation and filling
◼ Grade C- Preparation of solutions to be filtered
◼ Grade D- Handling of starting material
 Compounding aseptic isolator

◼ Aseptic manipulation is inside a closed, pressurised

environment and accessed via gloves
◼ Protects workers, unidirectional/turbulent air flow
and positive/negative pressure
 Laminar Flow Hoods
◼ Provide clean air to the working area
◼ Provide constant air flow- prevent room air entering
◼ Air flowing out- removes contaminants introduced by
operator
◼ Two types:
◼ horizontal flow- draws in air from above, filters it, then
forces it out the front of the working area of the hood
◼ vertical flow- more complicated, drawing air through the
front of the working area into the vent system at the front
of the working surface- 80% of this air is re-circulated and
the remainder expelled
Laminar Flow Hoods Cont.
 Personnel
◼ Minimum number in clean area- where possible inspection
& control should be outside
◼ Regular training-reference to hygiene and basic element of
microbiology
◼ Outside staff should be guided through and supervised
◼ Personal hygiene & cleanliness are essential
◼ Changing & washing should follow a written procedure
◼ Wristwatches & make-up should not be worn
◼ No outdoor clothing- room leading to grade B/C also should
change garment A/B
◼ Mask and gloves- change after each session
 Premises
◼ Clean areas- smooth & unbroken
surface using TSA plates
◼ Ceiling and walls are sealed properly
◼ No sink and drains in grade A/B
◼ Changing room should be fitted with
airlocks
◼ Filtered air supply should maintain
positive pressure
◼ Air-flow patterns do not present a
contamination risk- air sampling
TSB, TSA and total particle counts
◼ Warning system should indicates
failure
 Quality management
◼ Manufacturing unit- products are fit for purpose and
no risk to patient because of safety, quality or efficacy
◼ A comprehensive system of Quality Assurance (QA)
incorporating Good Manufacturing Practice (GMP)
and Quality Control (QC)
◼ It needs to be fully documented and its effectiveness
monitored (SOP)
◼ Adequately resourced with competent personnel,
suitable and sufficient premises, equipment and
facilities
 Quality Assurance
◼ Covers all matters which individually or collectively
influence the quality of products it involves auditing and
suggestion for changes
◼ QA should ensure:
◼ Medicinal products designed and developed following
GMP & GLP
◼ Managerial responsibilities are clearly defined

◼ Deals with in process controls & validation

◼ Deals with quality throughout their shelf life

◼ Training of pharmacist and technicians

 Good Manufacturing practice (GMP)
◼ It is part of QA which ensures that products are
consistently produced and controlled to the quality
standards for their intended use required by product
specifications
◼ GMP is concerned with production and QC
◼ Basic requirements for GMP:
◼ Manufacturing process are well defined
◼ Adequate premises and space
◼ Suitable equipment and services
◼ Suitable storage and transport
 Quality Control (QC)
◼ QC is that part of GMP which concerned with
sampling, specifications and testing with the
organisation, documentation and release procedures
are in placed
◼ Basic requirements for QC:
◼ Facilities, trained personnel and procedures are in placed
for sampling, inspection and testing starting materials, all
approved by QC
◼ Test methods are validated
◼ Records are made to prove that sampling, inspection and
testing procedures were actually carried out
 References
◼ European Community, Guide to GMP for Medicinal Products
and Active Pharmaceutical Ingredients, Annex 1, Rev. 1996,
Manufacture of Sterile Products 2003
◼ International Standard Organisation, Cleanrooms and
Associated ControlledEnvironments, Part 1, Classification of
Air Cleanliness,International Standard ISO 14644-1 (1999)
◼ Rules and guidance for pharmaceutical manufacturers 2007
◼ Medicines and Healthcare Regulatory Agency (MHRA)
website
◼ Pictures are taken www.globalrph.com and Envira website