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Process Robustness PQRI White Paper
Process Robustness PQRI White Paper
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE A PQRI White Paper
November/December 2006, Vol. 26 No. 6
The Product
Quality Research Process Robustness – A PQRI White
Institute (PQRI)
is collaborative Paper
effort between
the
pharmaceutical by PQRI Workgroup Members
industry, Michael Glodek, Merck & Co.; Stephen Liebowitz, Bristol-Myers Squibb; Randal McCarthy,
regulatory Schering Plough; Grace McNally, FDA; Cynthia Oksanen, Pfizer; Thomas Schultz, Johnson &
agencies, and Johnson; Mani Sundararajan, AstraZeneca; Rod Vorkapich, Bayer Healthcare; Kimberly
Vukovinsky; Pfizer, Chris Watts, FDA; and George Millili, Johnson & Johnson - Mentor
academia. One
of the purposes
of PQRI is to
promote Introduction Background
T
Objective There is a heightened emphasis on greater
discussion on he ability of a manufacturing process to process understanding in the pharmaceutical
current topics of tolerate the expected variability of raw industry. There is great incentive from a
interest in the materials, operating conditions, pro- manufacturer’s point of view to develop robust
pharmaceutical cess equipment, environmental condi- processes. Well understood, robust processes
tions, and human factors is referred to as ro- suggest greater process certainty in terms of
field. To that bustness. yields, cycle times, and level of discards. Lower
end, PQRI The objective of this paper is to unify under- final product inventories may be carried if the
commissioned a standing of the current concepts of process manufacturing process is reliable.
working group to robustness and how they apply to pharmaceu- There is a growing expectation from global
tical manufacturing. The paper also provides regulatory agencies that firms demonstrate a
develop a White recommendations on development and main- comprehensive understanding of their processes
Paper that tenance of a robust process. The concepts pre- and controls. The finalized FDA report entitled
discusses the sented here are general in nature and can “Pharmaceutical cGMPs for the 21st Century -
concept of apply to many manufacturing situations; how- A Risk-Based Approach” clearly expresses the
ever, the focus of the discussion is application expectation that firms strive for “the imple-
process of robustness principles to non-sterile solid mentation of robust manufacturing processes
robustness and dosage form manufacturing. The tools, case that reliably produce pharmaceuticals of high
how it applies to studies, and discussion presented in this paper quality and that accommodate process change
development, center around new product development and to support continuous process improvement.”
commercialization as, ideally, process robust- As evidenced by recent draft guidelines, the
scale up, and ness activities start at the earliest stages of other members of the ICH tripartite have also
manufacture of process design and continue throughout the adopted the philosophy embraced by this “Risk-
pharmaceutical life of the product. It is also recognized that Based Approach.” The eventual implementa-
products. concepts of robustness can be applied retro- tion of recommendations contained in ICH Q8
spectively to established products in order to and Q9 should establish the linkage between
enhance process understanding. “knowledge” and “associated risk.” An underly-
ing principle of ICH Q8 is that
Figure1. Proven an assessment of process ro-
Acceptable Range (PAR). bustness can be useful in risk
assessment and risk reduc-
tion. Furthermore, such an as-
sessment of process robustness
can potentially be used to sup-
©Copyright ISPE 2006
through the choice of manufacturing technology. Setting are not typically considered CPPs unless they also impact
appropriate parameter ranges for a robust process requires product quality.
consideration of the manufacturing technology selected. Spe- Most processes are required to report an overall yield from
cial considerations are needed for situations/processes where bulk to semi-finished or finished product. A low yield of a
the appropriate setting of one parameter depends on the normally higher yielding process should receive additional
setting of another. Well designed processes reduce the poten- scrutiny since the root cause for the low yield may be indica-
Figure 4. Case study example: Fishbone diagram for a direct compression tablet.
Appendix A
Potential Critical Process Parameters for Common Solid Dosage Form Unit Operations
Blending • Dry Mixing Time
• Blend Time • Wet Mixing Time
• Rotation Rate • Impeller Speed
• Agitator Speed • Chopper Speed
• Room Temperature, Humidity • Power Consumption
PROCESS PARAMETERS
API Pre- Feed Excipient
Blend Lube Particle Compression Compression Compressing Frame Particle
Quality Attributes Time Time Size Force Force Speed Setting Size Importance
Dissolution 1 7 9 1 9 1 3 1 10
Assay/ Potency 1 5 3 10
Uniformity 7 1 9 5 3 5 10
Appearance 1 3 3 3 5
Stability 1 3 7
©Copyright ISPE 2006
Yield 3 3
Ranking Total 95 95 187 10 126 134 90 60
Percent 13 13 25 1 17 18 12 8
Table B. Case study example: Prioritization matrix for a direct compression tablet (Note that this matrix is for the case study example only
and may not be all inclusive).
Design of experiments can often be a two-stage process, • the qualitative and quantitative composition of the prod-
involving screening experiments to identify main factors to uct
consider as well as response surface methodologies to refine • API, excipient specifications and functional attributes
the understanding of functional relationships between key • potential increased variability in the API as a result of
parameters and attributes. An example of a statistical DOE scale-up of the API manufacturing process
for the case study of a direct compression tablet is shown in • manufacturing process and controls, operator experience,
Table C. and skill sets
• Assessment of equipment, used at the development stage
Step 6: Confirm Critical Quality Attributes versus the identified commercial manufacturing equip-
(CQAs) and Critical Process Parameters (CPPs) ment, to identify batch sizes and operating parameters.
After a sufficient amount of process understanding is gained, This equipment assessment should also include equip-
it is possible to confirm the CQAs previously identified (step ment controls and tolerances.
2). In the case study for a direct compression tablet, the
critical quality attributes were dissolution, assay, tablet After CQAs and CPPs have been defined, the team should
uniformity, and stability. As defined in a previous section, a generate a plan for controlling CPPs. This may involve, but is
CPP is defined as a process input that has a direct and not limited to establishment of process operating limits, use
significant influence on a CQA. CPPs are typically identified of automation, procedural controls and specialized operator
using the functional relationships from step 5. In the case training and qualification. In addition, it is critical that the
study for a direct compression tablet, tablet press speed and knowledge transfer is well documented for the development
compression pressure were found to impact the CQA of and technology transfer phases through to the commercial
dissolution, and were identified as CPPs. In Figure 5, it can scale.
be seen that there is an optimum compaction pressure to
obtain the highest dissolution. In Figure 6, it can be seen that Run Compression. Press Speed Dissolution Disso SD
increasing the tablet press speed resulted in increasing Order Pressure (1000 tab/h) (Average %
variability in dissolution. (megaPascals) dissolved at 30 min)
These functional relationships can be used and various 1 350 160 83.12 2.14
optimizing strategies employed to identify optimal process
2 150 160 81.54 2.40
set points or operating regions for press speed and compac-
tion pressure. Suppose the product’s goal is to achieve an 3 250 280 96.05 3.73
average dissolution greater than 80% with less than a 5% 4 150 260 80.38 6.18
standard deviation on dissolution. One summary source 5 390 210 69.32 6.08
providing information on a potential operating region is an
6 250 140 94.81 1.14
overlay plot; see Figure 7 for the case study of a direct
compression tablet. This visual presents a predicted (yellow) 7 250 210 96.27 3.59
area of goodness where average dissolution is greater than 8 250 210 94.27 6.37
80% and simultaneously the standard deviation of dissolu- 9 110 210 70.76 4.03
tion is less than 5%. The area where either or both of these
©Copyright ISPE 2006
As presented in the manufacturing section, with more Monitoring the State of Robustness
manufacturing history and data over time, assessment of As R&D has established the desired operating range of
robustness can be ascertained. parameters and attributes, Manufacturing should monitor
both the parameters and attributes over time and review the
Process Robustness in Manufacturing information at a pre-determined frequency, with emphasis
The Research and Development (R&D) phase is character- on critical or key parameters.
ized by execution of a development plan consisting of a The state of robustness may be monitored through using
number of discrete experiments that are designed to develop Statistical Process Control (SPC) charts combined with capa-
a formulation, establish the proper manufacturing process, bility index calculations. SPC tools such as control charts can
and provide process and formulation understanding around be used to ascertain the process’ stability, provide warnings
the key relationships between parameters and attributes. of any potential problems, and to assess the state of control.
When the product is transitioned to Manufacturing, it will Capability indices assess the product or process ability to
most likely encounter a much wider range of variation on the meet specifications. To evaluate the true state of robustness,
parameters than seen in development. For example, at- information on process parameters and attributes should be
tribute variability may increase due to a wider range in collected as per a pre-determined SPC sampling plan. Pro-
incoming raw material parameters that cannot feasibly be cess control charts (trend chart, run chart) are constructed
studied in R&D. It is upon transfer to Manufacturing that and capability indices calculated.
assessment of the true process capability and robustness as
well as any process improvement or remediation will begin. • Run Chart/Trend Chart: A run chart or trend chart is an
Manufacturing yields a large amount of empirical process x-y plot that displays the data values (y) against the order
performance data that may be used for a variety of purposes. in which they occurred (x). These plots are used to help
It should be periodically analyzed to assess process capability visualize trends and shifts in a process or a change in
and robustness and to prioritize improvement efforts; the variation over time.
data should be reviewed during the improvement effort to
identify correlative relationships. Feedback to R&D may • Control Charts: Similar to a run chart, a control chart is a
occur during these activities to further build quality into the plot of a process parameter or quality attribute over time.
design process. Although Manufacturing may benefit from a Overlaid on the plot is information about the process
larger amount of empirical data, the ability to perform planned average and expected variability (control limits). Statisti-
experimentation is not trivial. There are other techniques cal probabilities form the basis for control chart rules that
that have been successfully utilized to further process under- help identify odd process behavior. Identifying and remov-
©Copyright ISPE 2006
standing and variability reduction. This section discusses ing assignable causes of variability to the extent that only
techniques that are applicable to analyzing data to determine smaller or common sources of variability remain produces
the state of process robustness and ensure the continuation a process that can be considered stable and predictable
of this state over time. over time, or under statistical control and producing con-
sistent output.
Plant-wide Variability Reduction Activities • Plant Layout: Along with other environmental factors of
In addition to the targeted improvement or remediation temperature, pressure, and humidity, etc., the general
activities just discussed, process variability may be reduced cleanliness, orderliness, and layout of an area provides an
through plant-wide process improvement initiatives aimed indirect effect on the variation of a product. Environmen-
at general sources of variability. Recent industry initiatives tal plans should be developed and maintained.
and programs targeted at variability and cost reductions and
efficiency and flow improvements include 6-sigma, lean manu- Conclusion
facturing, and even lean sigma. Creating a system that facilitates increased process under-
General sources of process variability include machines, standing and leads to process robustness benefits the manu-
methods, people, materials, measurement systems, and envi- facturer through quality improvements and cost reduction.
ronment. Examples of variability reduction/process improve- Table D summarizes the robustness roles by product life cycle
ment activities that address the general sources of variability along with useful tools for each stage. This system for robust-
and will lead to improved processes include: instrumentation ness begins in R&D at the design phase of the formulation
calibration and maintenance, gage R&R studies, operator and manufacturing processes; emphasis on building quality
skills assessment, general plant layout, and clearly written into the product at this stage is the most cost effective
work instructions. strategy. R&D quantifies relationships between the inputs
and outputs; the processes are established to produce the best
• Materials can be a significant source of process variability. predicted output with the targeted amount of variability.
It is important that the material functionality and specific Information about the process settings and key relation-
©Copyright ISPE 2006
physiochemical specifications are well understood. If some ships are communicated to Manufacturing. Upon transfer,
aspect of the material is critical, then is should be con- Manufacturing begins to verify R&D’s information on process
trolled. robustness through process monitoring and data analysis.
Both general and process specific improvement activities
help Manufacturing attain and maintain its goals.
Repeatability - The variability obtained with one gage used A Guide for Practitioners, New York: John Wiley & Sons.
several times by one operator. 18. Snedecor, G.W., and W.G. Cochran, (1980) Statistical Meth-
ods, The Iowa State University Press.
Reproducibility - The variability due to different operators
using the same gage on the same part. Quality Function Deployment
19. Madu, Christian N., (2000) House of Quality (QFD) In a
Minute, Chi Publishers.
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