Lecture 3 Pharmaceutical

Sterile and non-sterile
production of pharma
products
Lecture-2
 Microbiological contamination of pharmaceutical products and
drugs, carries a significant risk to the health of patients. The
presence of microorganisms has a direct impact on the integrity of
Introduction the product, its pharmacological effects and adherence to
treatment. In many cases, depending on the administration
method, contaminated medications can be life-threatening.
 The production of sterile medicinal products has special
requirements. These products must be produced in conditions that
ensure that they are pure. They must also be free from viable
organisms and pyroxenes with limited, or ideally no, particulate
Sterile Drug contamination. It is thus important that only carefully regulated
and tested procedures are used to manufacture sterile products.
Production  Owing to their special manufacturing requirements, sterile
medicines are prepared in special facilities known as clean rooms.
These rooms are designed to reduce the risk of microbial and
particulate contamination at all stages of the manufacturing
process.
 Terminal Sterilization
 Terminal sterilization is conducted after a drug has been
TYPES OF manufacturing and uses heat, radiation, and/or filtration, but this
is not always feasible and can have a detrimental effect on the
STERILE product and its container. As formulations become more complex,
a growing number of drug products cannot be terminally sterilized
PROCESSING and are less effective when exposed to heat or radiation.
 When terminal sterilization cannot be done, an aseptic
manufacturing process is the preferred method.
 Aseptic Fill-Finish is a process in which the drug product,
container, and container closure are first sterilized separately and
then brought together. The step of combining the product,
container and closure is done in a clean room and often uses
special equipment that is self-contained in a sterile environment.
TYPES OF The aseptic fill-finish process is challenging and complex.
STERILE  Due to complex production, and limited resources, it is common

throughout the pharmaceutical industry to partner with a CDMO.
PROCESSING CDMO's assist with sterile fill-finish development &
manufacturing.
i) Design of premises
 Sterile production should
be carried out in a
Clean And purpose-built unit
Aseptic Areas: separated from other
manufacturing areas and
General thoroughfares. The unit
should be designed to
Requirements encourage separation of
each stage of production
but should ensure a safe
and organized workflow.
ii) Internal Surfaces, fittings and floors
Clean And  Particulate, as well as microbial, contamination must be

prevented. To this end all surfaces must be smooth and impervious
Aseptic Areas: in order to:
General (1) prevent accumulation of dust or other particulate matter; and
Requirements (2) permit easily repeated cleaning and disinfection. Smooth

rounded coving should be used where the wall meets the floor and
the ceiling.
(iii) Services
 Clean and aseptic areas must be adequately illuminated; lights are best
housed in translucent panels set in a false ceiling. Electrical switches and
sockets must be flush with the wall or fitted outside. When required,
gases should be pumped in from outside the unit. Pipes and ducts, if
they must be brought into the clean area, must be sealed through the
Clean And walls. Additionally, in order to prevent dust accumulation, pipes and
ducts must be boxed in or readily cleanable. Alternatively, they may be
Aseptic Areas: sited above false ceilings.
General
 Sinks should be of stainless steel with no overflow, and water must be of
Requirements at least potable quality. Wherever possible, drains should be avoided. If
installed they must be fitted with effective, readily cleanable traps and
with air breaks to prevent backflow. Any floor channels should be open,
shallow and cleanable and connected to drains outside the area; they
should be monitored microbiologically. Sinks and drains should be
excluded from aseptic areas except where radiopharmaceuticals are
being processed when sinks are a requirement
(iv) Air Supply
 Filtered air is used to achieve the necessary standards; this should
be maintained at positive pressure throughout a clean or aseptic
area, with the highest pressure in the most critical rooms (aseptic
or clean filling rooms) and a progressive reduction through the
preparation and changing rooms; a minimum pressure differential
Clean And of 10 kPa is normally required between each class of room. A
minimum of 20 changes of air per hour is usual in clean and aseptic
Aseptic Areas: rooms. The air inlet points should be situated in or near the ceiling,
with the final filters placed as close as possible to the point of
General input to the room. Equipment or furnishings must be sited so as
not to interfere with laminar flow.
Requirements
v) Clothing
 Clothing worn in a clean area must be of non-shedding fibres;
polyester is a suitable fabric. Airborne contamination, both
microbial and particulate, is reduced when trouser suits, close-
Clean And fitting at the neck, wrists and ankles, are worn. Clean suits should
be provided once a day, but fresh headwear, overshoes and
Aseptic Areas: powder-free gloves are necessary for each working session.
General vi) Changing facilities
Requirements  Entry to a clean or aseptic area should be through a changing

room fitted with interlocking doors; this design acts as an airlock
to prevent influx of air from the outside. This route is for personnel
only, not for the transfer of materials and equipment. Staff
entering the changing room should already be clad in the standard
factory or hospital protective clot
vii) Cleaning and disinfection
 A strict, validated disinfection policy is necessary if microbial
contamination is to be kept to a minimum. Cleaning agents used
include alkaline detergents and ionic and non-ionic surfactants. A
Clean And wide range of chemical disinfectants is available. Clear, soluble
phenolics are commonly used for interior services and fittings.
Aseptic Areas: Disinfectants for working surfaces are alcohols (70% ethanol or
isopropanol) or, less commonly, chlorine-based agents such as
General hypochlorites. Skin may be disinfected with cationic detergents
Requirements such as cetrimide or chlorhexidine, usually formulated with 70%
alcohol to avoid the need for rinsing. Gloved hands may be
disinfected with these detergents or 70% alcohol. The former have
the advantage of offering residual activity. Rotation of different
disinfectants reduces the risk of the emergence of resistant
strains, but such rotation should be validated.
 Nonsterile processes are methods or procedures undertaken in an environment
where bioburden is controlled to safety levels based on product attributes, route
of administration, and target patient population. Non-sterile processes contrast
with sterile processes, in which the bioburden is essentially eliminated. The non-
sterile products listed below are ranked for potential risk of microbiological
contamination (from high to low). The same list applies to medical devices for
use in the same body areas (nasopharynx, vagina, skin, rectum, and mouth).
Non-sterile Nonsterile pharmaceutical products include:

 Metered-dose and dry powder inhalants
pharma  Nasal sprays
production  Optics
 Vaginal suppositories
 Topicals
 Rectal suppositories
 Oral liquids (aqueous)
 Liquid-filled capsules
 Oral tablets and powder-filled capsules
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Sterile and non-sterile

STERILE  Due to complex production, and limited resources, it is common

Clean And  Particulate, as well as microbial, contamination must be

General (1) prevent accumulation of dust or other particulate matter; and

Requirements (2) permit easily repeated cleaning and disinfection. Smooth

General vi) Changing facilities

Requirements  Entry to a clean or aseptic area should be through a changing

Non-sterile Nonsterile pharmaceutical products include:

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