Design, Trust & Control of Sterile Manufacturing

Obaid Ali & Roohi B. ObaidCivil Services Officers, Government of Pakistan

12th March 2016, Saturday, Karachi

08th

Technical Meeting / Forum

Sterile Manufacturing

Part II 2

What is Particulate Matter?

Mobile un-dissolved particles other than gas bubbles, unintentionally

present in the solutions

Ref: USP Chapter <788>

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

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

Sources of Particulate Matter in Injectable Drug Products

Environment Packaging materials

Solution & formulation components

Product-packaging

interactions

Process generated particles

Important Fact

Proper product development and appropriate manufacturing & packaging process design can successfully exclude

four out of five categories

Cont’d

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

Source Particulate Matter Intrinsic/Extrinsic

Environment (including personnel)

Dust, FibersBiologics-insect parts, microorganisms, pollensFibers of anthropogenic originHair SkinPaint/coating chipsRust Metal (non-product contact types)MineralsPolymers (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

Source Particulate Matter Intrinsic/ExtrinsicPackaging material Rubber

Glass PolymersSilicone

Intrinsic

Solution and formulation components

PrecipitatesOligomersDegradantsAgglomeratesUndissolved material

Intrinsic

Types & Sources of Injectable Particulate Matter

Cont’d

Source Particulate Matter Intrinsic/ExtrinsicProduct-package interactions

Glass lamellaeSilicaRubberPlastic

Intrinsic

Process generated particulate matter

Metal (e.g. stainless steel from processing equipment)Filter and consumable fibersGlass (from breakage events)

Intrinsic

Types & Sources of Injectable Particulate Matter

Clinical Effects of Injected Particulate Matter

Phlebitis Pulmonary emboli

Pulmonary granulomas

Immune system

dysfunction

Pulmonary dysfunction Infarction Death

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

Route of Administration

The route influences the

deposition of the injected particles

The total particle load administered

The overall risk to the patient

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

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

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

Intra-arterial Route of Administration

Particles injected IAArteries ↓ 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

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

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

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

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 formulationMetal

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

Patient Population

Patients with existing tissue

damage e.g. trauma, surgery or sepsis

Critically ill patients Neonates

At highest risk