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1-  Drug Product/manufacturing process design and development.

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Physical properties  include physical description (particle size, shape, and distribution), polymorphism, aqueous solubility as function of pH, hygroscopicity, and melting points.

Chemical properties  include pKa, chemical stability in solid state and in solution as well as photolytic and oxidative stability

Biological properties  include partition coefficient, membrane permeability, and/or oral bioavailability.

Generate a thorough  understanding of the material’s stability  under various processing and in vivo conditions.

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to  determine  the appropriate (salt and polymorphic) form of drug substance, to  determine  that the drug substance is stable in the presence of selected excipient (s) within the desired concentration range,  to  ensure  material’s stability under various processing and in vivo conditions, leading to an optimal drug delivery system .

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Full Scale product and process Development

Stages of Product/Process Development are summarized as follows:

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1-  Product design and characterization.   2-  Optimum formulation. 3-  Process design begins.

I-  Product Development  (Stage 1)  1X   Laboratory Batch

Following successful preformulation studies, the API is transferred to the formulation laboratories for preliminary product design and development studies.

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II -  Process Development , Stage 2  10X ,  Pilot Batch

Unit Operation Activity that deals with the processes that are essentially physical in nature such as mixing, milling, granulation, drying, compaction, and coating.

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Fig 1   Typical Flow Diagram for Tableting Ref: Pharmaceutical process validation

The majority of process development activities occur in this stage. *Define  (select)  unit operations and  , the  equipmen t used for the development of tablets.  *Define  critical process parameters (variables/factors) & measured responses (Critical Quality Attributes) for each unit operation.   *Establishes limits (numerical range) for the critical process parameters within which the quality of drug product is assured.

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Attributes  Physical, chemical or microbiological property of an input or output material.  Critical Quality Attributes (CQA) Physical, chemical or microbiological property that must be controlled either directly or indirectly to ensure quality of the product. Critical Process Parameter (CPP)  Process input (variable) that has a direct and significant effect on critical quality attributes when they are varied within normal operating range.

Acceptance criteria: 90%-110% of the labeled amount.

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Load size  -Amount of granulating agent -rpm -Granulation time

Granules that are not mixed long enough can form incomplete or weak granules (may have poor flowability and compression). Oppositely; overmixing can lead to harder granules and a lower dissolution rate.

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-Inlet temperature -Outlet temperature -Drying time & load.

High MC: 1) tablet picking or sticking to punch surfaces, 2) poor chemical stability. Overdried granules: could result in poor hardness and friability.

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Figure 1. Sticking of formulation to an unembossed punch

IN: Sticking and Picking in Pharmaceutical Tablet Compression: An IQ Consortium Review

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Bulk/tapped densities determination: ☺ Bulk density is used in determining the amount of powder or granules that can fit in equipment, such as a blender or a hopper on a tablet press or capsule filler.   ☺ Flow assessment: Poor flowability can lead to the inability to feed powder into the dies of a rotary tablet press and can also cause tablet weight variation.

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Particles size distribution *Bulk/tapped density

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*wt uniformity *Content uniformity *Hardness *Thickness *Friability *Disintegration time *Dissolution

-Granule feed rate -Precompression force -Compression rate

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