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Considerations For Strategic Partnering
With CRO/CMOs: Incorporating QbD Early
In Product Development Is Key To Success
A case study examining QbD in development and scale-up of ophthalmic dosage forms.
by Ron Connolly, Vaishali Ketkar, Amit Shah, and Veerarajendra (Raj) Yadwad
T
he pharmaceutical industry is continually looking to
accelerate and streamline the product development
process to bring new products to the market
efficiently. For the last few years the U.S. and EU
regulatory communities have worked together to develop
guidelines that encourage implementation of the principles
of Quality by Design (QbD) in the drug development
process. The QbD initiative is a science- and risk-based
approach to pharmaceutical process development and
manufacturing. Implementing QbD principles earlier in the
drug development program enhances the development
team’s understanding of critical control requirements
and encourages collaboration between product/process
development, quality, and manufacturing personnel.
Early implementation of QbD principles can improve
the collaborative efforts of CRO/CMOs and streamline the
knowledge transfer between firms. During the collaborative
development process, sponsors have the task of addressing
product quality, technical, and supply requirements with
their CRO/CMO, while attempting to foster continuous
improvement activities that can drive efficiencies in the
program. By utilizing the QbD platform from the initial
stages of formulation and process development, an
enhanced collaboration and partnership between sponsors
and service providers can be developed to streamline the
design and scale up of clinical trial material (CTM) and
commercial manufacturing processes.
QbD In Pharmaceutical Development
Incorporating QbD in the early stages of product development
can lead to a product and process that is easy for scale-up
with fewer challenges and obstacles at pilot and commercial
scale manufacturing. According to ICH Q8 guidance, “quality
cannot be tested into products, i.e. quality should be built in
by design.” There are several advantages of incorporating a
QbD approach into the pharma development program:
n Facilitates quicker development of new products by
utilizing a development platform or standard regimen of
experimental activities;
n Prevents/minimizes failures during manufacturing,
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and when failures do happen, a scientific justification
can be derived based on past experience;
n Reduces manufacturing costs due to fewer failures
and improved process efficiencies;
n Fosters continuous improvement in product and
process during scale-up activities;
n Provides relevant information to the regulatory
agencies for a quicker review and approval process.
This article presents a practical example of employing QbD
in the development and scale-up of a generic ophthalmic
dosage form. The study demonstrates how the core principles and guidelines contained in ICH Q8 (R2), Q9, and Q10
can be applied to product realization programs.
Development Approach
For the case study described below, a stepwise approach
was adopted to arrive at scalable formulations. The key steps
during the development phase were:
Establish a quality target product profile (QTPP)
Identify quality attributes critical to the product
being developed
n Perform risk analysis and identify critical materials,
critical processes, and critical process parameters (CPPs)
that affect the critical quality attributes (CQAs) of the drug
product
n Propose control strategies to establish specifications
for raw materials, packaging components, manufacturing
process steps, and process parameters
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The goal of the case study was to collaborate with the
sponsor and develop a generic equivalent of a marketed
ophthalmic product. The team worked with the sponsor to
design a formulation and process development plan within
the QbD framework that can be scaled up at the sponsor’s
commercial manufacturing site.
CQA, CPP, And Risk Analysis
As the first step, the development team established the QTPP
of the generic product by analyzing the results of reverse
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Product development workflow for ophthalmic solutions case study
engineering experiments with the reference-listed drug
(RLD). The CQA/CPPs of the drug product were identified
through risk analysis. Three CQAs (physical and chemical
stability, product viscosity, and droplet size/delivered dose)
and one CPP (associated with the thermal sterilization process used for sterilization of the viscosity-building polymer
solution) were considered to greatly risk product quality.
Reverse engineering of the RLD via in-house methods
yielded a target concentration of the viscosity-building
polymer. Based on the viscosity range of the analyzed RLD,
three different grades of the polymer were evaluated during
prototype formulation development. Various formulations
prepared at target polymer concentrations resulted in a product at the expected viscosity range; however, the formulation
presented three major challenges for the development team:
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Selection of a sterilization process
Control of solution viscosity post-sterilization
Control of product viscosity under long-term storage
Because the active pharmaceutical ingredient (API) was
observed to be chemically unstable under thermal sterilization, an aseptic filtration process was evaluated to develop
a suitable process flow that could achieve a sterile finished
product. Three different grades of a viscosity-building polymer were evaluated for sterile filtration under various processing conditions (e.g. filter surface area, filtration rates, and
filtration pressure). Based on study observations, only one
polymer grade was identified as suitable for aseptic filtration.
With this understanding, appropriate filtration parameters
were identified and prototype product formulations utilizing
this polymer grade were evaluated for stability. However,
stability study data indicated the drug product prepared by
aseptic filtration using this polymer grade was not capable of
maintaining the required physical stability profile during storage. This then meant reverting to the previously evaluated
polymers and examining other means of producing sterile
product that could maintain the required parameters.
Three different thermal sterilization processes were
evaluated. One of the attempted thermal sterilization
processes was observed to yield a product with adequate
physical stability upon storage. Thus, to achieve the target
drug product viscosity and maintain API stability in the
formulation, the drug product manufacturing process was
split into two stages to allow for aseptic filtration of the
solution containing the API and thermal sterilization of the
solution containing the viscosity-building agent.
Other than API solubility, no significant high-risk factor
was identified for the compounding process used to
prepare the active solution. On the other hand, the process
parameters used for the thermal sterilization of the polymer
solution were identified to be high-risk factors that could
impact the drug product viscosity. Studies were carried
out to evaluate the effect of CPPs associated with thermal
sterilization process on the polymer solution viscosity poststerilization. Various CPPs of the thermal sterilization process
that affected the viscosity of the polymer solution were:
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Amount of bulk solution
Temperature distribution within the bulk solution
Time required to reach the sterilization temperature
Dwell time
Time taken to cool the bulk solution post-sterilization
All of the above parameters were observed to affect
polymer viscosity post-sterilization. Based on the correlation
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of the CPPs and viscosity of the polymer solution pre- and
post-thermal sterilization, ranges were identified for the
concentration of polymer stock solution, characteristics of
the polymer materials, and thermal sterilization process
parameters. Through our experimentation, we discovered that
in order to obtain the target finished product viscosity, control
on CPPs alone was insufficient. Hence, implementation of
raw material specification control was critical to achieving
the target product viscosity. The CPP ranges identified
in the study along with raw material specifications were
recommended to support the scale-up studies.
The third CQA identified as a potential risk was droplet
size/delivered dose of the finished product. The delivered
dose is impacted by a combination of various factors such
as packaging components and drug product viscosity. The
primary packaging materials and variability of the packaging
specifications contribute to risk. Therefore, this aspect had to
be contemplated in concert with the selection of the polymer
materials described in the second CQA. Various containerclosure systems were evaluated for material of construction
and for drop size using the prototype formulations. The
delivered dose of the product was able to be controlled
by optimizing the formulation composition, drug product
viscosity, and the selection of the appropriate containerclosure system.
After optimizing formulation composition and compounding
processes, the compounded product was evaluated for
physical and chemical stability using the selected containerclosure system. Several attributes were considered during the
evaluation of the container-closure systems, such as material
of construction, drop size, container-closure sterilization
process, and product interaction (e.g. particulate matter,
leachables, product adsorption, etc.). During our evaluations,
we determined that factors such as the additives used in the
container-closure materials and the treatment of the materials
during sterilization had an impact on the interactions with
this drug product formulation, which in turn posed additional
container/closure specifications and selection criteria to be
employed in the program.
Control Strategy
As noted in the previous sections, physical and chemical
stability, product viscosity, and drop size were identified as
the high-risk CQAs for this drug product. To ensure chemical
stability of the product, a multistep sterilization process was
developed for the bulk solution — aseptic filtration for the
bulk solution containing the API and thermal sterilization
for the polymer solution that was aseptically combined with
the API solution. The product drop size was controlled by
selection of appropriate dropper tip and container materials,
in addition to the product viscosity. Container-closure
specifications such as resin additives and sterilization process
were established to ensure physical and chemical stability
of the drug product. A control strategy (listed below) was
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implemented for the polymer solution to ensure that the final
viscosity of the finished product is maintained upon longterm storage.
n Define viscosity range of the polymer (addresses lot to
lot variation)
n Establish in-process viscosity specification for the
polymer solution at the compounding, post clarification
filtration, and post-thermal sterilization steps
n Establish thermal sterilization process specifications for bulk
solution load size, process times, and process temperatures
n Define viscosity range of the final finished product
Conclusion
The case study illustrates that a product development
strategy that incorporates QbD can result in an optimized
formulation and a robust process with established design
space. This approach improves communications between
development partners and provides for a uniform platform
of CQAs and process parameters that are communicated
and agreed upon between the teams. This in turn
leads to a product that has a high potential for success
during scale-up and commercialization. Further, the data
generated during development can assist regulatory
agencies when reviewing the product. n
References
1. Guidance for Industry, PAT – A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
2. Guidance for Industry, Q8 (R2), Pharmaceutical Development
3. Guidance for Industry, Q9, Quality Risk Management
4. Guidance for Industry, Q10, Pharmaceutical Quality System
5. Guidance for Industry, Process Validation: General Principles and Practices
Ron Connolly, BS, is Sr. VP and GM of GMP Consulting Services for Frontage
Laboratories, Inc. Mr. Connolly has been involved in more than 25 FDA inspections,
and has consulted for numerous worldwide pharmaceutical companies. Mr. Connolly
previously served on the scientific affairs committee of the GPhA and numerous GMP
task force groups at Wyeth Pharmaceuticals (Pfizer).
Vaishali Ketkar, Ph.D., is director of product development and CTM manufacturing
for Frontage Laboratories, Inc. With more than 12 years of experience in the
pharmaceutical industry, Dr. Ketkar’s expertise falls in formulation development for
parenteral, ophthalmic, oral, and topical dosage forms for IND and ANDA applications
and clinical trial material manufacturing for Phase I and Phase II studies. Dr. Ketkar
received her Ph.D. from the University of Iowa.
Amit Shah, Ph.D., is principal scientist of product development and CTM manufacturing
for Frontage Laboratories, Inc. Dr. Shah has more than six years of experience in the
pharmaceutical industry and is responsible for developing immediate release, controlled
release, and delayed release oral solids dosage forms and manufacturing finished
products for Phase I and II trials. Dr. Shah has developed new and generic drug products
utilizing techniques such as hot-melt granulation, tablet-in-tablet, tablet-in-capsule, and
multiparticulate systems.
Veerarajendra (Raj) Yadwad, Ph.D., is senior director of CTM manufacturing for
Frontage Laboratories, Inc. Dr. Yadwad has more than 20 years of experience in
biopharmaceutical research and development, technology transfer, and commercial
GMP manufacturing, including sterile-fill, sterile-finish, and lyophilization. He received
his Ph.D. from Karnatak University in India.
Acknowledgements
Authors would like to acknowledge Dr. Bo Jiang, principal scientist, and formulation
scientists Jeff Lankford, Harry Pham, and Anuj Gupta as well as the analytical
development team at Frontage for their contribution to the work presented in the article.
Authors would like to thank Dr. Dongmei Wang, Sr. VP and GM, CMC, for her contribution
toward critical review of this article.