Quality by Design – Implementation and Challenges

The pharmaceutical industry has implemented regulatory practices
such as Process Analytical Technology (PAT), Good Manufacturing
Practices (GMP), and now Quality by Design (QbD) to make sure that consumers get only quality and safe
pharmaceutical products.

The FDA defines QbD as a “scientific, risk-based, holistic and proactive approach to
pharmaceutical development.”  It is a deliberate design effort from
product conception through commercialization that provides a full
understanding of how product attributes and process relate to product
performance.  QbD calls for a clear understanding of the processes in
order to define the design and control parameters that determine the
limits and operating sphere.

QbD helps improve the products and processes in the manufacturing industry in a scientific
manner and through a meticulous and well-designed plan. Joseph Juran,
who introduced the practice, said that it is possible to achieve quality
through right planning. He also said that based on quality planning,
the quality and process deviations can be mapped. This is because QbD is
more scientific and engineering based, unlike the previous regulatory
practices that are empirical in nature (Quality by Testing).

Implementation of QbD

It is important for the pharmaceutical company to have a thorough grasp of
the physiochemical characteristics of their drug as well as the
important process parameters in order to implement the QbD.  An
understanding of the process will be helpful in establishing the
relationship between the characteristics of the drugs, process
limitations, the material characteristics of the API (Active
Pharmaceutical Ingredients) and the excipients that can be mixed with
the drugs.

The different levels of implementation of the QbD are as follows:

1. Thorough Understanding of the Process

The understanding of the manufacturing process has to be developed on the
basis of multivariate analysis and prior data. The process parameters
and the crucial quality aspects have to be described and documented.
Then systems for identifying the origin of variability have to be

2. Quality by Design

The process should be developed to be flexible and capable of minimizing
deviations, keeping in mind the need to control the product’s critical
quality attributes. It should be adjustable within it design space.
Multivariate analyses and statistical modeling will be useful to
determine which quality attributes are the most sensitive and if there
are interactions between attributes.  This is a multi-disciplinary
activity so the teams involved in QbD implementation will have people
with different specializations who are trained in QbD modeling and
simulation and who have a common goal to develop a process that can be
well controlled.

3. During the Manufacturing Process

The parameters and specifications determined as critical during modeling
simulations or pilot studies will be monitored and assessed in real time
to manage the quality of the product.

4. Constant Improvement

It is important to ensure continuous improvement by constantly collecting data and analyzing them.

Implementation of QbD is not a guarantee of the efficiency of pharmaceutical
companies. The top management and the key decision makers have to be
trained to feel comfortable in decision making, based on the data

Benefits of QbD

The major benefits of implementing the QbD are the following:

•    The risks become less and manageable

•    Real-time quality assurance testing ensure faster release of products

•    Improvement in product quality and lower product deviation rate

•    Faster transfer of data between development and operations

•    Lower costs of operation

•    Lesser number of onsite regular inspections

•    Effective complete lifecycle management

•    Continuous improvement in company’s overall processes

There are significant challenges for QbD implementation.  The pharmaceutical
industry spends huge amounts of money in research and development to
improve manufacturing processes.  It can take a large investment in
resources and materials to conduct the research and to collect data for
statistical analysis.  Some pharmaceutical companies have reservations
because of the high costs involved in the implementation of the system.

its current form, the QbD has more features compared to other systems
and this poses the biggest challenge. The workers assigned to implement
the system will take more time to develop a thorough understanding of
the processes and complete certain tasks. The complexity of the QbD can
also pose documentation and management issues.  Moreover, the
pharmaceutical industry has to define as to what complete understanding
of QbD processes means, how workers can acquire this understanding and
clarify as to how one can know that a process specification is crucial.

conclusion, there are significant efforts being taken by the pharmaceutical industry to
constantly improve its processes for the benefit of the consumers and
stakeholders. However, the industry must carefully assess as to what is
feasible and reasonable for them and be aware of the costs involved
before starting down this road.

In spite of the potential extra costs, PharmaDirections decided to use the QbD philosophy when they developed a electronic cGMP manufacturing execution system with electronic batch records. This system is InstantGMP.  The quality system structure
was designed in coordination with the development of the database
software so GMP compliance could be built into the application.  The
extra time and cost paid off since there is now a manufacturing system
that is easy to implement and use.

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