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					                        Physical Transformations
Problem 1. Accelerating Drug and Product Technologies (ADAPT) &
Bioenhancement -Problem Statement
Due to the energy and mass challenges associated with pharmaceutical manufacturing,
pharma companies are striving to simplify manufacturing operations where possible. In
the formulation area, this means 2 things:
    1) reducing the number of unit operations in secondary manufacturing
    2) using bioenhancement methods (such as amorphous formulation through spray
       drying, nanomilling, co-crystals) to reduce the amount of API required to deliver
       an adequate dose to the patient.

Exemplification of Problem

An example of this problem is illustrated by GSK’s ADAPT program:
The vision of ADAPT is that:
1) By 2012, 75% of immediate release oral products will use simplified manufacturing
processes (3 formulation components and up to 3 formulation process steps) suitable for
effective, rapid progression to commercialisation

2) By 2012 we would create platform technologies that will enable GSK to speed the
delivery of oral in-licensed compounds and CEDD or CEEDD developed compounds

These are aimed to reduce costs, increase efficiency and minimize environmental impact.
ADAPT is organized in clusters with Rapier (i.e. capsules containing either API alone or
as a simple blend with 1-2 excipients), Simplification of Oral Dosage Forms and
Bioenhancement as three specific clusters.

Currently, evaluation of various ADAPT approaches has been based on technical
feasibility and simplification of number of unit processes involved e.g. from wet
granulation tablets to simple blends filled into capsules. The overall mass and energy
efficiency needs to be taken into account to ensure that by simplifying the secondary
process or combining the primary and secondary streams there is no negative impact on
total sustainability. Currently, we do not have sufficient data to model the outcome.

Similarly for bioenhancement, although it is accepted that by enhancing bioavailability
and exposure, the daily dose can be reduced thereby improving the sustainability of the
primary process, the impact of the more complex secondary process e.g. wet bead milling
& spray drying or using more complex carriers such as PEG and dissolving/suspending
the active in the excipient on mass and energy efficiency and thus the total effect is not
well understood.
Expected Output of Research

Part A. A theoretical model with consistent generic assumptions on finished dose form
characteristics (eg weight and dose strength) that;
   1. Calculates ADAPT operation mass and energy efficiencies (this could be limited
       to Rapier Capsules and Direct Compression tablets at this stage)
   2. Calculates operation mass and energy efficiencies for a given bioenhancement
       scenario of 50% (i.e. halving the dose) for wet bead mill/spray
       drying/blending/encapsulation process and liquid filled capsules

Part B. Through experimental research, physical properties measurement & estimation,
and theoretical modeling, identify suitable technologies for particle engineering of the
API to allow:
   a. Bulk density modification for capsule filling, thus eliminating the need for
       granulation with excipients, blending, drying and milling
   b. Production of micron and sub-micron particles without the need for Spiro Jet or
       Bead Milling. (technologies to be investigated include Slurry Milling, and
           c. Isolation by filtration via centrifugation of micron and submicron particles
               (avoids spray drying)
           d. Isolation Granulation (Spherical Agglomeration of micro / nano particles
               by crystallization, Quasi-emulsion Solvent Diffusion crystallization)
           e. Simultaneous classification and crystallization

GSK could likely provide model compounds for this work. The work will most likely
require a collaboration between pharmacy and engineering.

Part C. Characterise the capsule filling operation, understand what parameters are
critical for scale up and robust performance, and identify and measure what are the
optimum physical properties of the API or API and excipients that will ensure a
successful capsule filling operation.
Problem 2. Bioenhancement through co-crystals, amorphous
formulation, targeted delivery, or other alternative methods
Most pharmaceutical new chemical entities have bioavailability limitations due to poor
solubility, poor permeability, or both. This results in several sustainability problems:
    1) there is a high attrition rate among drugs in development due to poor exposure,
        increasing R&D costs and generating large amounts of drug which are eventually
        not used.
    2) When a drug does show efficacy and make it to market, low bioavailabilities
        require high doses of active ingredients. Much of the active ingredient is ‘wasted’
        and ends up in the environment as excreted mass.

Exemplification of Problem
It is common for certain drugs, particularly antivirals for the treatment of HIV, to have
doses well in excess of 1 g per day. Most of the drug is not used to treat the disease, but
is used to ensure adequate exposure for a therapeutic benefit. This causes both a pill
burden on the patient and a large amount of drug that is wasted to the environment.

Over time, drug attrition rate has increased with molecular complexity (molecular weight,
chirality, functionalization). Within GSK, attrition rates from candidate selection to
commercial manufacture are in excess of 95%. Certain drugs , such as Talnetant and
GW640385, have shown some activity but have not reached exposure levels high enough
to judge whether a therapeutic effect is possible, despite extremely high doses.

These types of problems are especially typical of BCS class II and IV compounds. In
some instances, nano-milling has been attempted but even this has achieved limited
results. Targeted delivery approaches have rarely been demonstrated.

Expected Output of Research
We would like to understand the in vitro and in vivo benefits from
bioenhancement/targeted delivery for BCS class II and IV compounds. Using a model
substrate and custom, structured approaches, the following would be expected:
   1) A structured approach to delivering bioenhancement solutions for BCS II and IV
   2) Exemplification across several compounds BCS II and IV
   3) A clear assessment of the benefits delivered by the bioenhanced/targeted delivery
GSK could likely provide model compounds for this work. The work will most likely
require a collaboration between pharmacy and engineering.

An expected outcome of this research would be an industrializable solution for
bioenhancement which offers clear lifecycle benefits over the current state (e.g.,
micronization or nanomilling of drug substance).
Problem 3 – Continuous Physical Transformations

There is pressure to reduce costs and increase efficiency in secondary manufacturing
(e.g., preparation of drug product capsules, tablets, etc..). In addition, there is pressure to
reduce environmental impact. To remain competitive in a highly competitive market, we
must seek to develop more intensified, safe, yet environmentally-friendly processes.
Given a regulatory framework for continuous processing, the key question is whether it
offers benefits compared to batch manufacturing. Selection of continuous processing
over batch manufacturing appears to be driven by two factors: economics and process

Typical pharmaceutical secondary manufacturing has excess batch capacity in solid oral
dose form manufacturing, so the economic justification for a switch from batch to
continuous is not straightforward. Operational benefits, write-off costs for excess
capacity as well as strategic issues must be considered.

Exemplification of Problem
The focus of the research should be in two areas.
   1. Traditional processes, e.g. roller compacted & wet granulated, film coated tablets.
   2. New processes, e.g. filling of simple blends into capsules.

The case for secondary continuous processing in R&D has been made & accepted. A
more efficient QbD approach and avoidance of scale-up have resulted in significant
reductions in FTE & API required to develop new drugs.

It is known in manufacturing that batch operations afford long manufacturing lead times,
poor process reproducibility & poor yields. However, the vision of a continuous
manufacturing factory is and its impact on these factors is poorly defined. Are there
dedicated product lines running 24/7, or should a line be able to produce bulk product for
2, 3, 4…..API’s? Should the line be flexible – plug & play to support different unit
operations for different products? Should we attempt to run continuously for months, or
would a week be sufficient (better yield, reduced washing)?

Hence the economics of continuous processing are not well defined for pharmaceutical
industry application. For example, for small volume products, a small scale, batch
processor will perform perfectly well.

Expected Output of Research
   1. The business case for various scenarios of secondary continuous processing in a
      GMP environment with PAT deployed should be explored.
   2. In addition, the business case economic scenarios for coupling primary and
      secondary should be explored – final stage or full synthesis.
   3. An appreciation of the regulatory aspects affecting the scenarios should be
      factored into the analyses.
Problem 4. – Transformation efficiency of API into
respirable particles to the patient
Future inhalation systems need to be more efficient in all aspects of manufacture and
device design, in order to maximise the transformation of API into respirable particles
delivered to the patient.

Secondary manufacturing processes used to manufacture inhalation dosage systems have
variable efficiency, in terms of the API mass which is transformed into product. These
efficiencies are highly dependent upon the kind of delivery system used e.g. DPIs (drug
product inhalers), nebulisers and other aqueous systems, pMDIs. (metered dose inhalers)

Once the manufacturing process is complete, different balances are achieved between the
amount of API released from the device to the patient and the amount retained in the
device. In addition, transformation of the dose delivered to the patient into respirable
API particles is low and highly dependent upon the delivery system used.

Most current inhalation devices use small molecules but in future increasing use of large
molecules is likely.

As a consequence, inhalation systems need to be more efficient in all aspects of
manufacture and device design, in order to maximise the transformation of API into
respirable particles delivered to the patient.

Exemplification of Problem
 In general API loss during secondary manufacture has not been well studied. Depending
on the intended delivery system, multiple unit operations need to be considered to cover
all categories of inhalation device, e.g., micronising, blending, filling, device assembly,
packaging, spray drying, nanoparticle production, solution manufacture, wet-bead
milling, microfluidising and sterilisation.

Other aspects of the inhalation system need to be considered. For example some DPIs
may deliver <20% of the API dose to the patient’s lung. The rest is either swallowed by
the patient or retained within the inhalation device. This means that a significant amount
of the drug is either lost or non-therapeutic. There exists an opportunity to increase the
efficiency of the delivery system and several companies are investigating energy assisted
systems based on air pulses or ultrasonic vibration

API from the synthesis into the final product typically involves dissolving up the API,
crystallization, isolation, drying, micronization and conditioning before it can be blended
with lactose and used in a DPI. The process from final step of synthesis to particles
suited for purpose can take several months. Transforming IG API to particles-fit-for-
purpose (respirable, narrow distribution, crystalline) that is scale independent is a
desirable target where many unit operations could possibly combined into a single unit
operation. Size reduction is a fundamental process in the development of inhaled
products. Typically micronization is used but is in general limited to the particles greater
than 1.5um. Opportunities exist in incorporating nanoparticles in various inhaled
delivery systems (DPIs, MDIs, nebulizers) which haven’t been fully exploited. There
are two general particle engineering approaches to create nanoparticles, bottom-up and
top-down. Both approaches have the potential to improve particle size control, particle
morphology and possibly improving the efficiency of inhaled delivery systems.

Expected Output of Research
Analysis of different size reduction methods or delivery systems.. For example
    Identification of methods to achieve size reduction to respirable size or
       nanoparticle size ranges from top-down approaches ideally scale independent and
       potentially continuous in nature. Include energy, cycle time, waste reduction and
       cost analyses
    Identification of methods to achieve size reduction to respirable size or
       nanoparticle size ranges from bottom-up approaches ideally scale independent
       and potentially continuous in nature. Include energy, cycle time, waste reduction
       and cost analyses
    Identification of novel approaches to improve the mass efficiency and
       sustainability of conventional bead milling technologies in the generation of
    Identification of methods of enhancing the delivery efficiency of dry powder
       inhalers using energy assisted approaches which would be independent of the
       patient effort.

Problem 5 – Process Efficiency Gains and Simplification in the
Recovery of Nanoparticles.
Nanoparticles of some pharmaceutically active compounds are recognized as a viable
means through which their biological exposure in humans can be increased in order to
produce the desired therapeutic effect.

These nanoparticles can be produced through a variety of means in which energy is
supplied to larger particles, breaking them down into smaller particles. The process is
repeated until the desired size of nanoparticles is obtained. In most commercial
processes, this operation takes place in an aqueous medium in which the particles are
suspended while subjected to energy. When the process is completed, the water is
removed through spray drying, leading to recovery of the active compound as a powder
in the spray dryer.
Exemplification of Problem

The current process, commercialized as described above presents several problems and
disadvantages which make it inefficient from an energy and cost perspective, while also
making it non-optimal for the drug product being developed.

From the energy and cost perspective: since the active compound is suspended in an
aqueous medium, that medium is removed by spray drying. In a typical process, the
water content of the suspension is of the order of 80%. The thermal energy requirements
to remove 80% of the water from commercial batches of drug substance is very
significant. In addition, because the spray drying process is time consuming, each batch
can take several days to process in a continuous operation.

From the drug product standpoint: the drug substance powder recovered within the spray
dryer is very fine, and comprises loose aggregates of the nanoparticles. This fine powder
has poor flow and compaction properties, and therefore requires that additional materials
(excipients) be added in significant quantities to make them suitable for processing into
capsules or tablets. In a typical tablet containing nanoparticles of API produced by this
method, it would not be unusual for the excipient content to be 75%-80%. This material
constitutes an extra cost, and yet does not eliminate the processing difficulties of
nanoparticles into tablets

Expected Output of Research

GSK has developed a novel process to isolate nanoparticles from suspension, using
agglomeration principles instead of spray drying. This process has the potential to
contribute significantly to Green and Sustainability goals as it is further developed and
scaled up.

The areas of interest at this time which would benefit from further evaluation of the new
nanoagglomeration process are as follows:

              Energy balance analysis with related cost improvements relative to spray
              Sustainability footprint analysis
              Manufacturing cycle time and cost analysis
              Related impact on drug product formulation and processes, including
               excipient quantities as well as drug product manufacturing operation

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