By Bikash Chatterjee and Warford Reaney
Pharmatech Associates, Inc.
Introduction
The recent emphasis on continuous improvement, operational excellence and Process
Analytical Technology (PAT) within the pharmaceutical and biotech industries has
driven us to evaluate the basic tenets of our approach to quality. Historically,
the ability to ensure that a drug will meet its intended form, fit and function
has been achieved through the combined application of quality infrastructure (SOP’s,
policies, specifications), qualification or validation (commissioning, IQ, OQ,
PQ process Validation) and Testing (in-process and final release). Despite this
rigid environmental approach, the number of drug recalls continues to rise, escalating
from 176 in 1998 to 354 in 2002 [US CDER website]. In a break from tradition,
the FDA recognized that the methods that lead to this problem could not be part
of the solution. In 2002 the FDA issued its revised cGMP guidance document entitled
Pharmaceutical cGMP’s for the 21st Century- A Risk Based Approach. This
guidance advocated a shift in industry reliance on a rigid punitive quality structure
to achieve regulatory compliance (with increasing failures) toward a more rigorously
scientific argument for product development, quality and production. The revised
guidance for the 21st Century is included as part of Presidential Executive Order
13329; an order that is designed to encourage innovation in manufacturing and
includes PAT. As inventing, developing and bringing new therapies to the marketplace
has long been considered a core strength of the pharmaceutical and biotech industry,
and given the increasing pressure and scrutiny from patient, shareholder, government
and regulatory entities, the industry has never been more driven to look at their
core business practices for solutions.
Quality Systems
Figure 1
The integration of these systems is designed to ensure through a combination of
design, sampling, testing and documentation that product manufactured under these
systems will meet their regulatory commitment for form, fit and function. The
challenge within the industry has been that due to the realities of drug discovery
in the current marketplace, too little emphasis is placed on the design and characterization
elements of the product development lifecycle and too much reliance on inspection
and verification/validation. With this weak foundation, regardless of the strength
of the downstream cGMP quality system and checks, there is a failure mode that
is inherent due to the lack of characterization and thus understanding of a product’s
underlying chemical /physical/ biopharmaceutical properties.
PAT
The intent of PAT was to advocate a more scientific and methodical approach to
product development, scale-up and production. The impact of PAT will be felt in
all sectors of the organization, if applied correctly, will increase granularity
in the quality and quantity of data being created throughout the product development
lifecycle. This data becomes the basis for process understanding and ultimately
ensuring product quality. In the PAT guidance document issued by FDA the agency
discusses several of the key elements required to be successful in deploying PAT.
Specifically, the guidance document discusses PAT Tools, the need for Process
Understanding, Risk-Based Management, Integrated Systems Thinking and Real-Time
Product Release. The reduced time and operational cost of taking a product from
the end of manufacturing to the marketplace has captured both the imagination
& interest of the industry.
Figure 2
Many pharmaceutical and biotech organizations capture this information as a byproduct
of their manufacturing and operational systems but have no clear plan for utilizing
the data. PAT will require the planned generation and effective utilization of
all of this data in order to be able to reduce the risk associated with the manufacturing
process variation
The current industry development approach requires that a process be “locked
down” once it is validated. This means any and all improvements to equipment,
procedures and processes must go through change control and, in cases where
a significant change to the original validated state has occurred, may require
re-submission to the agency. It also means that when processes vary unexpectedly
there is a reluctance to address the variation for fear of impacting the validated
state. In the current system, deviations from the process require an investigation
and corrective action plan (CAPA). The objective of a CAPA is to identify the
root cause of the deviation before implementing the corrective action.
Real-Time Product Release
Figure 3
The FDA guidance document3 describes PAT as: “A system for continuous
analysis and control of manufacturing processes based on real time measurements
or rapid measurements during processing, of quality or performance attributes
of raw and in-process materials and processes to assure end product quality at
the completion of the process.” The lure of Real-Time Product Release (RTPR)
has moved the industry forward faster technologically than in any period in recent
memory. It was not that long ago (the1980’s) that the industry was dabbling in
the possibilities of Near Infrared (NIR) Spectroscopy as a surrogate to HPLC only
to have the agency rebuff any attempts to demonstrate comparability. Now FT-NIR,
FT-IR, Raman and Mass Spectroscopy are being integrated in-line with process and
production equipment to accelerate release testing.
The unexpected byproduct of this has been the shift to technology that ensures
process compliance. In and of itself, this is not a bad development. Enhancing
the sophistication of control schemes brings greater light to the stability
of the process, can manage risk and increase the probability of success. However,
to be fully effective, it does require a thorough understanding of key process
variables and their influences. Without this understanding, there can be no
managing of the risk of product failure. The challenges in integrating PAT with
manufacturing hardware are significant. Sampling technology, cleanability, assay
specificity, accuracy and linearity and comparability to bench top methods and
previous production methods must all be addressed before proceeding to implementation.
Blending Case Study
In a recent PAT deployment a blender was equipped with in-line hardware in an
effort to determine Content Uniformity of the API and key rate controlling excipient.
The process flow is shown in Figure 3. The project was driven by intermittent
dissolution failures in the product. Data revealed that 1/3 of the tablets failed
S1 testing, while 1out of 12 tablets failed S2 (Figure 4). Subsequent analysis
found that the tablets that failed dissolution had significantly different amounts
of lubricant required for the formulation. The PAT study attempted to integrate
in-line FT-NIR analytical technology in the final blending stage. The data were
correlated against the bench top method that utilized ICP-MS.
Once in-line correlation was established a series of DOE’s were initiated to
determine the optimum blending conditions. The subsequent dissolution variation
was significantly reduced.
Root Cause Analysis
It would seem the project was a success. The process variation associated with
slow dissolving tablets was significantly reduced and an in-line correlation with
the bench top assay method was established. The problem with this solution was
that the root cause of the problem was two fold. The DOE data confirmed that the
manufacturing parameters for the blending operation were not optimum. Re-optimizing
the blending time and conditions significantly reduced process variation. However,
the unanticipated second factor of root cause variation was a result of the raw
materials. Further investigation revealed that the lubricant was purchased through
a distribution reseller who purchased its raw material from multiple excipient
suppliers. The specifications around the lubricant were not sufficient to ensure
the material would perform reproducibly within the process. So, despite the successful
integration of FT-NIR into the blending process, the gap in raw material -- and
thus overall characterization -- left a clear potential for atypical behavior.
Conclusion
PAT represents the single most significant change to drug development in the last
30 years. Other industries have been driven toward PAT due to customer or market
pressure. Unlike those industries, biopharma companies have the unique opportunity
to leverage their existing investments in science and technology to impact their
core business of bringing drugs to market. However, in preparing for PAT it is
important not to be blinded by the technological opportunities, as they are only
a part of the PAT solution. Only by the complete understanding and characterization
of key variables will it be possible to develop and implement solutions which
will anticipate product performance and realize both the compliance benefit of
PAT as outlined in the agency guidance, but also the financial benefit of having
a faster, cheaper delivery to market.
References:
1CDER Guidance for Industry, Quality Systems Approach to Pharmaceutical Good manufacturing Practices Regulations, September 2004.
2Geoffroy, Jean-Marie, Use PAT to Gain a Fundamental Understanding of Your Process and Then Mover Forward to Knowledge Development, Pharmaceutical Engineering, January/February 2004.
3CDER Guidance for Industry, Pharmaceutical cGMPs’ for the 21st Century, September 2004.
4Woodcock, Janet, The Concept of Pharmaceutical Water, American Pharmaceutical Review, November/December 2004.
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Laboratory Compliance: Making The Grade 
