This document discusses particulate matter in injectable drug products and the associated risks. It defines particulate matter and classifies it as either intrinsic or extrinsic. The key sources of particulate matter are the environment, packaging materials, the solution/formulation, product-packaging interactions, and the manufacturing process. The route of administration, particle size and shape, particle composition, number of particles injected, and patient population all impact the clinical effects and risks to patients, with intravenous administration posing the greatest risk. Particle size below capillary diameter, aluminum and metal particles are especially hazardous. Critically ill, neonatal, and patients with tissue damage are most vulnerable. Proper product development, manufacturing, and highly controlled filling areas are needed to minimize risks

1. Design, Trust & Control of
Sterile Manufacturing
Obaid Ali & Roohi B. Obaid
Civil Services Officers, Government of Pakistan
12th March 2016, Saturday, Karachi
08th
Technical Meeting /
Forum
Sterile
Manufacturing
Part II
2

2. What is Particulate Matter?
Mobile un-dissolved particles other than
gas bubbles, unintentionally
present in the solutions
Ref: USP Chapter <788>

3. Classes of Particulate Matter
Intrinsic Particles
• Originally associated with
the solution that were
either not removed by
filtration or precipitated
out of the solution
Extrinsic Particles
• That enter the container or
solution during
manufacturing
Ref: Groves, M.J. Parenteral Products; Hindemann Medical Books, Ltd. London, 1973

4. Ref: USP Chapter <1788>
Intrinsic Particles
• associated with the
package, formulation
and/or assembly
process, and capable
of change upon aging
Extrinsic Particles
• They are additive,
foreign, unchanging,
and not part of the
formulation, package
or assembly process
Classes of Particulate Matter

5. Sources of Particulate Matter in Injectable Drug Products
Environment
Packaging
materials
Solution &
formulation
components
Product-
packaging
interactions
Process
generated
particles

6. Important Fact
Proper product development and
appropriate manufacturing & packaging
process design can successfully exclude
four out of five categories
Cont’d

7. Important Fact
Particulate matter sourced from the environment
(5th category) can only be excluded by use of
highly controlled filling areas rather by an
intimate understanding of the product, process &
container closure system

8. Source Particulate Matter Intrinsic/Extrinsic
Environment
(including personnel)
Dust,
Fibers
Biologics-insect parts, microorganisms, pollens
Fibers of anthropogenic origin
Hair
Skin
Paint/coating chips
Rust
Metal (non-product contact types)
Minerals
Polymers (unknown source)
Glass (e.g. carry over from components)
Extraneous material (e.g. carry over from rubber
stopper components)
Extrinsic
Types & Sources of Injectable Particulate Matter
Cont’d

9. Source Particulate Matter Intrinsic/Extrinsic
Packaging material Rubber
Glass
Polymers
Silicone
Intrinsic
Solution and formulation
components
Precipitates
Oligomers
Degradants
Agglomerates
Undissolved material
Intrinsic
Types & Sources of Injectable Particulate Matter
Cont’d

10. Source Particulate Matter Intrinsic/Extrinsic
Product-package
interactions
Glass lamellae
Silica
Rubber
Plastic
Intrinsic
Process generated
particulate matter
Metal (e.g. stainless steel from processing
equipment)
Filter and consumable fibers
Glass (from breakage events)
Intrinsic
Types & Sources of Injectable Particulate Matter

11. Clinical Effects of Injected Particulate Matter
Phlebitis
Pulmonary
emboli
Pulmonary
granulomas
Immune
system
dysfunction
Pulmonary
dysfunction
Infarction Death

12. Clinical Effects of Injected Particulate Matter
Patient risk associated with injected particulate matter
depends upon a number factors such as:
• Route of administration
• Particle size and shape
• Number of particles injected
• Particle composition
• Patient population

13. Route of Administration
The route influences the
deposition of the injected particles
The total particle load administered
The overall risk to the patient

14. The risk of systemic reaction
is low, if the administration is
via IM or SC route as
• The delivered volume (overall
particle load) is relatively small
• The ability of particles to migrate
far from injection site is negligible
The IV route carries the
maximum possibility of
• Delivering greater volume of fluids
• Broader dissemination &
deposition of particulate matter
throughout the body
Route of Administration

15. Intravenous Route of Administration
Particles
injected
IV
Venous system
(veins ↑ in size
in direction of
blood flow)
Heart
Pulmonary
artery
Lungs
Capillary
diameter 6-8 um
Particles > 6-8 um
remain in
pulmonary
capillaries
Smaller particles
deposit in organs
e.g. liver & spleen
Cont’d

16. Intravenous Route of Administration
Processed by the
phagocytic cells of the
reticulo-endothelial
system
Phagocytic overload of the
reticulo-endothelial system
by large number of particles
has potential to block the
system
Lead to secondary
infections in a
debilitated host

17. Intra-arterial Route of Administration
Particles injected IA
Arteries ↓ in
size in direction
of blood flow
Large particles
pass through
arterioles &
capillaries
May cause
occlusion
affecting blood
flow
Smaller particles are capable of
blocking terminal arterial vessels
More detrimental than
larger particles
Large particles occlude
arterioles due to ↓
collateral blood supply
available to the affected
tissue
Cont’d

18. Intra-arterial Route of Administration
Intravascular Injection of
corticosteroid formulation
containing particles is linked with
adverse CNS sequelae in humans
versus non-particulate steroid
formulations
A study on pigs injected in vertebral
artery with particulate or non-particulate
based steroids showed brain stem edema
& significant tissue damage in pigs
receiving particulate containing steroids

19. Particle Size and Shape
The shape as well as size of particle is important in
determination of potential for harm
The total particle load is also an important factor to
consider
Various animal studies with particulate containing
injections showed deposition in lungs and liver, as
well as in spleen & kidneys
Cont’d

20. Particle Size and Shape
Adverse event reports & autopsy results are the only
source of information about the effect of larger
particles on patient populations
Visible particulate matter composed of calcium salt
precipitates in drug admixtures have caused a number
of serious clinical events

21. Particle Composition
• The most common contaminant
• Derived from manufacturing process, reaction
of drug with CCS, or produced by opening
glass ampoules
• Can cause phlebitis, pulmonary granulomas,
systemic inflammatory response syndrome,
adult respiratory distress syndrome
Glass
• Most common source is processing equipment
• Contaminate the raw materials used in drug
product formulation
Metal

22. Particle Composition
• The most common dangerous contaminantLead & Chromium
• Toxicity in premature infants is linked to TPN
admixtures
• Resulted in FDA regulations related to Al content of
drug products for TPN
Aluminum
• Product recalls due to stainless steel particles in lipid
emulsions requiring high shear force have
necessitated the development of modified
manufacturing process & visual inspection methods
to detect potentially harmful levels of metal particles
Stainless steel

23. Patient Population
Patients with
existing tissue
damage e.g. trauma,
surgery or sepsis
Critically ill patients Neonates
At highest
risk