Precautions in handling, storage and manufacture of pharmaceutical products containing antibiotics by dr. sanaullah aslam

Precautions in handling, storage and
manufacture of pharmaceutical products
containing antibiotics.
Submitted by: Dr. Sanaullah Aslam
Dr. Sanaullah Aslam

Anti- infectives are drugs that can
either kill an infectious agent
or
inhibit it from spreading.
Anti-infectives include
antibiotics and antibacterials,
antifungals, antivirals
and antiproatozoans.
Anti-infective agent
Dr. Sanaullah Aslam

Antibacterials
are classified on the basis of
chemical / biosynthetic origin into:
• Natural
• Semisynthetic, and
• Synthetic
Dr. Sanaullah Aslam

Antibacterials
Antibiotics
An antibiotic is an agent
produced by a microorganism
that
either kills
or inhibits
the growth of other microorganisms
Dr. Sanaullah Aslam

Antibacterials
Antibiotics
Beta-lactam antibiotics
Beta lactam antibiotics are
one of the largest group of antibacterial products
used clinically
to combat the most resistant pathogens.
Dr. Sanaullah Aslam

Antibacterials
Antibiotics
It basically includes the following drugs:
1.Penicillins
(e.g., Benzyl penicillin, Methicillin, Nafcillin, Cloxacillin,
Dicloxacillin, Ampicillin, Amoxicillin, Bacampicillin, Pivampicillin,
Carbenicillin, Ticarcillin, Azlocillin, Mezlocillin, Piperacillin)
Dr. Sanaullah Aslam

Antibacterials
Antibiotics
2. Cephalosporin (e.g., cephalexin, cefaclor)
3. Penems (e.g., imipenem, meropenem)
4. Carbacephems (e.g., loracarbef)
5. Monobactams (e.g., aztreonam)
Dr. Sanaullah Aslam

• Drug cross-contamination is
the contamination of one drug
with one
or more different drugs
• Penicillins and non-penicillin beta-lactam are
sensitizing agents, and
cross-contamination can initiate
drug-induced hypersensitivity reactions in people
Background
Dr. Sanaullah Aslam

• Hypersensitivity reactions may be
serious and
life threatening.
• Defining the minimal dose
below which allergic responses are unlikely to occur
is difficult.
Background
Dr. Sanaullah Aslam

• No suitable animal or receptor testing models exist
to predict human sensitivity
• Threshold for allergic response is
extremely low and
difficult to detect.
Background
Dr. Sanaullah Aslam

• Manufacturers should assess
health risks and
establish stringent controls
(including appropriate facility design and operation)
to prevent cross-contamination
• The health risk of sensitization
and cross-reaction
is difficult to predetermine
for beta-lactam products and intermediates,
and may be highly variable within the population.
Potential Health Risks
Dr. Sanaullah Aslam

• There are definite concerns
with cross-reactivity (cross- sensitivity)
between
beta lactam products in the population
• IgE - mediated hypersensitivity reactions
are a primary concern
due to associated morbidity and mortality
Dr. Sanaullah Aslam

• The potential health hazard
non-penicillin beta-lactam drugs is
similar to that of penicillin
• Some beta-lactam intermediate compounds
and derivatives possess
sensitization and
cross–reactivity properties
Dr. Sanaullah Aslam

• Beta-lactam
chemical manufacturing processes including,
but not limited to,
fermentation and synthesis
may create
beta-lactam intermediates
or
derivatives
with unknown health consequences
Dr. Sanaullah Aslam

• Some beta-lactam antibiotics
have no potential for cross - reactivity
with beta-lactams of other classes,
whereas some may exhibit
sensitizing activity
as derivatives
before the incorporation of side chains
that confer antibacterial activity.
Dr. Sanaullah Aslam

• Manufacturers can prevent
cross-contamination
of finished products
and APIs
by following
current Good Manufacturing Practices (cGMP)
Manufacturing cGMPs
Dr. Sanaullah Aslam

• cGMPs
are not specific
to Active Pharmaceutical Ingredients,
however,
FDA does recommend
following the ICH Q7 Guidance
–Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredient
Manufacturing cGMPs
Dr. Sanaullah Aslam

• Finished pharmaceuticals
are required
to comply with
cGMP regulations
under 21 CFR parts 210 and 211
Manufacturing cGMPs
Dr. Sanaullah Aslam

• Several cGMP regulations
directly address facility and equipment controls
and cleaning:
• §211.42(d) -Separate or defined manufacturing areas or
control systems necessary to prevent contamination or “mix-
ups” during manufacturing, processing, packaging, storage,
and holding
Manufacturing cGMPs
Dr. Sanaullah Aslam

• - §211.176
-Requirement to test
non-penicillin drug products
for penicillin
(when the possibility of exposure
to cross contamination exists)
and prohibits manufacturers from
marketing such products if
detectable levels of penicillin are found
Manufacturing cGMPs
Dr. Sanaullah Aslam

• §68 211.46(d)
-Manufacturers must completely separate
air handling systems
for penicillin
from those used for
other drugs for human use.
Manufacturing cGMPs
Dr. Sanaullah Aslam

• - §211.176
-Requirement to test
non-penicillin drug products
for penicillin
(when the possibility of exposure
to cross contamination exists)
and prohibits manufacturers
from marketing such products
if detectable levels of penicillin are found
Manufacturing cGMPs
Dr. Sanaullah Aslam

• §68 211.46(d)
Manufacturers must completely separate
air handling systems for penicillin
from those used for
other drugs for human use.
Manufacturing cGMPs
Dr. Sanaullah Aslam

• FDA considers separation of production facilities
for penicillins to be cGMP
and manufacturers expected to treat
sensitizing non-penicillin
beta lactam-based products similarly
• Under cGMPs
-separate buildings may not be necessary
but firms must structurally isolate
and dedicate
production facilities and equipment
Assessment of Facilities
Dr. Sanaullah Aslam

• There can be
a "building within a building“
i.e. two buildings are not required.
However,
every aspect of the operations
must be separate
including physical barriers
and separate air handling systems.
Dr. Sanaullah Aslam

• Manufacturing
restricted to a specific class of beta-lactam
compound (e.g. the cephalosporins)
would generally not mandate
separate facilities and air handling systems,
and could permit production campaigning
and cleaning as sufficient
• Need well established written procedures and controls
Dr. Sanaullah Aslam

• The penicillin’s, cephalosporins,
Penems, and Carbacephems
are a characteristic bicyclical core structure,
which is believed to initiate
allergic reactions.
Allergic / sensitivity reactions
Dr. Sanaullah Aslam

• Unfortunately,
most of the Beta lactam antibiotics are
associated with
hypersensitive reactions.
• As per information available in medical journals
about 7% to 8 % of individuals in world
are allergic to penicillin’s and
the allergy may be
a life threatening for an individual
Allergic / sensitivity reactions
Dr. Sanaullah Aslam

The major challenges in
designing, manufacturing and packaging
beta lactam facilities are as follows:
1. How to physically and
functionally isolate
Beta lactam Facility
from adjacent facilities
GMP Requirements in handling, storage
and manufacture of beta-lactam antibiotics:
Major challenges
Dr. Sanaullah Aslam

2. How to design
Man and material Flow
for handling and processing
the Non Beta lactam products?
3. How to design
the HVAC, spillage control
and decontamination systems?
Major challenges
Dr. Sanaullah Aslam

4. How to detect,
measure
avoid the cross contamination?
5. How to control process wastes
and
how to dispose off the same safely?
Major challenges
Dr. Sanaullah Aslam

Tips for designing, manufacturing,
packaging and monitoring
beta-lactam facilities
Major challenges
Dr. Sanaullah Aslam

• Dedicated facility and AHU
for manufacturing
each class of beta-lactam antibiotics.
• When Beta lactam and non Beta lactam production occurs
in the same building
the penicillin area must be structurally
and functionally isolated.
Tips for designing, manufacturing, packaging
and monitoring beta-lactam facilities
Dr. Sanaullah Aslam

• Nothing shall be common
between
the two facilities.
• Proper procedures
to restrict misuse, spillage, dusting
and occupational health hazardous
from Beta lactam products are undertaken.
Dr. Sanaullah Aslam

• Close monitoring of gowning,
sampling, weighing, mixing, filling
and packing
of Beta lactam products
for likely cross contamination of other products.
• Validate LAF hoods
and filter systems
used for handling Beta lactam Products
Dr. Sanaullah Aslam

• Ensure adequate and
efficient decontamination of vessels,
equipments, machines,
used for processing Beta Lactam products.
• Ensure that airlocks, change rooms,
pass boxes
are robust in construction
to avoid cross contamination of Beta lactam products.
Dr. Sanaullah Aslam

• Ensure that entry and exit doors,
materials and personnel,
have an interlock mechanism
prevent the opening
of more than one door at a time.
Dr. Sanaullah Aslam

• Ensure that
the man/material entry and exit facilities
are independent.
The exit side
must incorporate air showers
to take off Beta lactam residues f
rom the operator’s body.
Dr. Sanaullah Aslam

• Ensure that facility is
maintained at a negative air pressure
to the environment.
This will restrict environmental contamination
with beta lactam drug residues.
• Ensure that the premises (and equipment) are
appropriately designed and installed
to facilitate batch to batch cleaning
and decontamination.
Dr. Sanaullah Aslam

• Ensure that
the man and material flow
is properly designed
to avoid undue exposure
and spreading of the Beta lactam residues.
Dr. Sanaullah Aslam

• Ensure that the activities
carried out in the vicinity of the site
are closely monitored
for likely contamination
• Ensure that
the HVAC outlets
of Beta lactam section does not cross match
with HVAC inlet
of No Beta lactam facility.
Dr. Sanaullah Aslam

Ensure that
Beta lactam facility is a well - sealed structure
with no air leakage
through ceilings, service penetrations,
door, windows and ventilators.
Dr. Sanaullah Aslam

• Ensure that
HVAC system is appropriately designed,
and maintained
to ensure protection of
product, personnel and the environment
with Beta lactam residues.
• The direct venting of the air
to the atmosphere is strictly prohibited.
Dr. Sanaullah Aslam

• Ensure that
there is adequate light in the facility
to indicate deposition of Beta lactam residues
on walls, roof and machines in place.
Dr. Sanaullah Aslam

• Ensure that
the air is exhausted to the outside
only through HEPA filters
and not recirculate
except to the same area,
and provided that further HEPA filtration is used
Dr. Sanaullah Aslam

• Ensure that
where possible,
Single - pass air - handling systems
with no recirculation are provided.
Dr. Sanaullah Aslam

• Ensure that
airlocks and pass - through hatches
are effectively covered by AHU
to provide necessary air pressure cascade
and containment.
• The final air lock or pass-through hatch bordering
on non-GMP area should be
at a positive pressure
to prevent the ingress of contaminants into the facility.
Dr. Sanaullah Aslam

• Ensure that
operators leaving the containment area
pass through air showers,
to remove dust particles
from their garments.
Dr. Sanaullah Aslam

• Ensure that
HEPA filters in the supply air system
should be terminally mounted
to avoid cross - contamination from backflow
in the event of a supply airflow failure.
• Ensure that
biosafety cabinets or glove boxes
are used to handle
highly potent Beta lactam products
Dr. Sanaullah Aslam

• Ensure that
air supplied in the facility
confirm to international standards
and is consistent with the zone concepts
and the product specific protection required.
Dr. Sanaullah Aslam

• Conduct risk analysis
for potential cross-contamination
of the non beta lactam products
from beta lactam
or contamination of one Beta lactam
with other Beta lactam Product.
• Do ensure that
the exhaust systems are protected
from two banks of HEPA filters in series
Dr. Sanaullah Aslam

• Ensure that
Installed filter leakage tests
should be performed in accordance with
ISO 14644-3
• Ensure that
all air exhaust points are located
as far as possible
from air entry points in the facility.
Dr. Sanaullah Aslam

• Ensure that
all contaminated filters are
suitably disposed off and
records are maintained
• Ensure that
all Portable Vacuum Cleaners,
Portable Dust Collector are
fitted with HEPA Filters
Dr. Sanaullah Aslam

• Do Ensure that
the operators are fully decontaminated
during entry and exist
through over head and
lateral air showers operating at high speed
Dr. Sanaullah Aslam

• Ensure that
Air Showers are subjected to
appropriate qualification
• Ensure that
Liquid and solid waste are
suitably disposed
to avoid environmental contamination
Dr. Sanaullah Aslam

• Design Beta lactam and
No Beta lactam Facilities separately.
• Further, avoid
common entrance, stores,
and packaging and dispatch areas.
• Don’t appoint
common QA personnel
for collecting samples
Dr. Sanaullah Aslam

• Restricted movement of personnel
from Beta Lactam area
to Non Beta lactam areas
• Check that
walls ,roofs and machine surfaces
are regularly monitored
for residual amounts of Beta lactam Products
Dr. Sanaullah Aslam

• Ensure that
the organizational structure,
procedures, processes, resources,
and activities are adequate
to maintain integrity of Beta lactam products
• Dedicated storage area
for Beta lactam Actives
and Finished products
Dr. Sanaullah Aslam

• Conduct
Cross Contamination audits
and Annual Cross Contamination Review.
• Maintain MSDS
for all Beta Lactam Materials/Products
Dr. Sanaullah Aslam

• Use Monolithic Epoxy Coated Floorings
in core production areas
to discourage deposition
of Beta lactam Dust on floor
• Insulate
all door, windows, hatches
for possible leakage of beta lactam residues
Dr. Sanaullah Aslam

Precautions in handling, storage and manufacture of pharmaceutical products containing antibiotics by dr. sanaullah aslam

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