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MANUFACTURING

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Q7.116 In such case, a MVDA model or other type of control model are
anticipated to be established as high impact model, as those models
will be part of control strategy which directly impacts batch release
and stability. Therefore, for development of such advanced integrated
pharmaceutical manufacturing control systems, at design level, it will
be necessary for the industry to consider several important features
such as technical feasibility, scientific validity, control robustness, and
fitness for intended use, etc.
At the modeling level, it will be important for the industry to consider
specific technical details such as rationale, protocol, and supporting
data for model development, validation, maintenance, update, and
change control (e.g., data traceability, data-pretreatment algorithms
used, and version control), in order to ensure that executed control has
been validated scientifically. For additional technical details regarding
PAT-oriented modeling, referred to FDA draft NIR guidance117 for basic
considerations of NIR model development, validation, and update as
appropriate. For general PAT techniques involved, refer to ASTM E55.01
Process understanding and PAT system management, implementation
and practice118 as appropriate. Refer to the most recent update of ASTM
E2891-13119 for linkage between PAT model and manufacturing; Refer to
the applicable user manual of the data system integrated.
To enhance the system integration performance, it is suggested the
industry considers the following factors: (1) Establishing a system
performance evaluation matrix ; (2) Conducting system sensitivity
and robustness analysis for both internal and external disturbance to
CPPs and CQAs which would have global impacts; (3) Establishing a
user-friendly interface for visualization, data analysis, reporting, etc.;
(4) Build-in data storage capacity, data security, and data backup
function, etc.
Considering it is a conceptual open challenge, it is hoped that this
discussion could stimulate more discussions from the community,
such that collaborative effort can be in place to foster pharmaceutical
manufacturing innovation and advanced manufacturing to meet
unprecedented challenges for the ultimate purpose to promote and
protect public health under a rapidly changing global environment.

Concluding Remarks
Significant progress has been made in many aspects which boosted
innovation in pharmaceutical development, manufacturing, and
quality assurance since the publication of the FDA PAT Guidance in
2004. In this article, key achievements of four critical areas during PAT
implementation are summarized, with emphasis on process monitoring
and control strategy development. In terms of actual implementation of
integration of PAT and data systems for pharmaceutical manufacturing
and quality improvement, significant progress has been made in
several vital areas, including but are not limited to (1) Identification of
critical product attributes (CQAs) and critical process parameters (CPPs)
during pharmaceutical development as a first step of advanced process
monitoring and control implementation; (2) Applying PAT for control
strategy establishment across scale; (3) Applying PAT for continuous
manufacturing control strategy establishment across scale; (4) Applying

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automatic control and data systems for integrated manufacturing system
and flexible manufacturing system (FMS) control strategy establishment,
etc. In addition, some of the unprecedented opportunities for applying
PAT for continuous improvement during development, scale-up, and
post-approval change control of Immediate Release (IR) and Modified
Release (MR) dosage forms has been discussed briefly. Furthermore, to
tackle the overwhelming data challenges anticipated during control
strategy establishment for advanced manufacturing implementation,
such as the dynamic nature of data generation in terms of volume,
velocity, and variety, apparently it is necessary to integrate PAT and
data systems for effective manufacturing process control and product
quality improvement. In the spirit of stimulating more discussions in this
rapidly evolving area, with illustrations of two scenarios of integration
of PAT and data system for manufacturing process control, challenges
and opportunities along with certain considerations on quality, risk
mitigation, and compliance have been discussed. Last but certainly
not least, it is important to recognize that the knowledge gained from
pharmaceutical development, real-time or frequent monitoring, and
control strategy establishment could constitute the critical elements of
modern pharmaceutical manufacturing control and release, enhance
the science and risk-based regulatory assessment, and help the public
to gain access to medicines with improved quality.

Acknowledgement
I sincerely acknowledge very insightful comments from colleagues,
especially Dr. Stelios Tsinontides and Commander Mahesh
Ramanadham, to improve the article. The technical feedback on data
system and presentation of Figures 2-3 from Tina Huang at OSIsoft
is greatly appreciated. Moreover, I thank the FDA CDER Regulatory
Science and Review (RSR) program for funding support on regulatory
utilities of PAT in pharmaceutical development and manufacturing,
the FDA CDER OPQ Office of Testing and Research (OTR) and the FDA
CDER OPQ Immediate Office for providing opportunities to conduct
laboratory-based PAT researches, and countless colleagues and
friends in the pharmaceutical community for their support during my
professional career development.

References
1.

FDA Guidance for Industry. PAT-A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance. September 2004. (accessed on
05/05/2020)

2.

Janet Woodcock. The Concept of Pharmaceutical Quality. American Pharmaceutical
Review. Nov Dec 2004, 1-3.

3.

FDA Guidance for Industry. Q8(R2) Pharmaceutical Development. November 2009.
(assessed on 05/05/2020)

4.

FDA Guidance for Industry. Process Validation: General Principles and Practices. January
2011. (accessed on 05/05/2019)

5.

FDA Guidance for Industry (Draft). Quality Considerations for Continuous Manufacturing.
February 2019. (accessed on 05/05/2020)

6.

FDA Guidance for Industry: Q10 Pharmaceutical Quality System. (accessed on 05/04/2020)

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