ASTM E2475-10
(Guide)Standard Guide for Process Understanding Related to Pharmaceutical Manufacture and Control
Standard Guide for Process Understanding Related to Pharmaceutical Manufacture and Control
SCOPE
1.1 The purpose of this guide is to establish a framework and context for process understanding for pharmaceutical manufacturing using quality by design (QbD) (Juran, 1992; FDA/ICH Q8). The framework is applicable to both active pharmaceutical ingredient (API) and to drug product (DP) manufacturing. High (detailed) level process understanding can be used to facilitate production of product which consistently meets required specifications. It can also play a key role in continuous process improvement efforts.
1.2 Process Analytical Technology (PAT) is one element that can be used for achieving control over those inputs determined to be critical to a process. It is important for the reader to recognize that PAT is defined as:
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Designation: E2475 − 10
StandardGuide for
Process Understanding Related to Pharmaceutical
Manufacture and Control
This standard is issued under the fixed designation E2475; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope E2474 Practice for Pharmaceutical Process Design Utilizing
Process Analytical Technology
1.1 The purpose of this guide is to establish a framework
E2617 Practice for Validation of Empirically Derived Mul-
and context for process understanding for pharmaceutical
2 tivariate Calibrations
manufacturing using quality by design (QbD) (Juran, 1992;
2.2 U.S. Government Publications:
FDA/ICH Q8). The framework is applicable to both active
FDA/ICH Q8 Pharmaceutical Development
pharmaceutical ingredient (API) and to drug product (DP)
FDA/ICH Q10 Pharmaceutical Quality Systems
manufacturing. High (detailed) level process understanding
U.S. FDA PAT Guidance Document, Guidance for Industry
can be used to facilitate production of product which consis-
PAT—A Framework for Innovative Pharmaceutical
tently meets required specifications. It can also play a key role
Manufacturing and Quality Assurance
in continuous process improvement efforts.
1.2 Process Analytical Technology (PAT) is one element
3. Terminology
that can be used for achieving control over those inputs
3.1 Definitions of Terms Specific to This Standard:
determined to be critical to a process. It is important for the
3.1.1 critical inputs, n—critical process parameters and
reader to recognize that PAT is defined as:
critical raw material attributes for a given process.
“{a system for designing, analyzing, and controlling manufacturing through
timely measurements (i.e., during processing) of critical quality and performance American Society for Quality
attributes of raw and in process materials and processes, with the goal of
3.1.2 empirical, adj—any conclusion based on experimental
ensuring final product quality. It is important to note that the term analytical in
PAT is viewed broadly to include chemical, physical, microbiological, data and past experience, rather than on theory.
mathematical, and risk analysis conducted in an integrated manner. The goal of
3.1.3 expert system, n—an expert system is a computer
PAT is to enhance understanding and control the manufacturing process{”
(U.S. FDA PAT)
program that simulates the judgment and behavior of a human
oranorganizationthathasexpertknowledgeandexperiencein
1.3 This standard does not purport to address all of the
safety concerns, if any, associated with its use. It is the a particular field.
3.1.3.1 Discussion—Typically, such a system contains a
responsibility of the user of this standard to establish appro-
priate safety and health practices and determine the applica- knowledge base containing accumulated experience and a set
of rules for applying the knowledge base to each particular
bility of regulatory limitations prior to use.
situation that is described to the program. Sophisticated expert
2. Referenced Documents
systems can be enhanced with additions to the knowledge base
or to the set of rules.
2.1 ASTM Standards:
E456 Terminology Relating to Quality and Statistics
3.1.4 first principles, n—a calculation is said to be from first
E2281 Practice for Process Capability and Performance
principles, or ab initio, if it starts directly at the level of
Measurement
established laws of physics and does not make assumptions
such as model and fitting parameters.
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
3.1.5 mechanistic, adj—(1) of, or relating to, theories that
ofPharmaceuticalandBiopharmaceuticalProductsandisthedirectresponsibilityof
explain phenomena in purely physical or deterministic terms: a
Subcommittee E55.01 on Process Understanding and PAT System Management,
Implementation and Practice. mechanistic interpretation of nature.
Current edition approved April 15, 2010. Published August 2010. DOI:10.1520/
E2475-10.
Juran, J., Juran on Quality by Design: The New Steps for Planning Quality Into
Goods and Services, Free Press, New York, N.Y., 1992. AvailablefromU.S.GovernmentPrintingOfficeSuperintendentofDocuments,
For referenced ASTM standards, visit the ASTM website, www.astm.org, or 732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http://
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM www.access.gpo.gov.
Standards volume information, refer to the standard’s Document Summary page on Available from American Society for Quality (ASQ), 600 N. Plankinton Ave.,
the ASTM website. Milwaukee, WI 53203, http://www.asq.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2475 − 10
3.1.6 process capability, n—statistical estimate of the out- 4.3.2 Accordingly, the development of process understand-
come of a characteristic from a process that has been demon- ing should be treated as an ongoing process. Learning should
strated to be in a state of statistical control. E2281 continue throughout the product and process life cycle to
improve the level of process understanding to include process
3.1.7 process inputs, n—the combination of all process
parameters and other factors (for example, environmental,
parameters and raw material attributes for a given process.
changes of scale, changes in raw materials, changes in person-
3.1.8 process understanding, v—to recall and comprehend
nel) which may have changed or which may have newly
process knowledge such that product quality can be explained
emerged since the time the process was first commissioned.
logically or scientifically, or both, as a function of process
Work to enhance process understanding continuously through-
inputs and respond accordingly.
out the life cycle of the product and process can provide
assurance that the process will continue to have an acceptably
3.1.9 residual error, n—the difference between the observed
result and the predicted value (estimated treatment response); low risk of producing out of specification results.
4.3.3 Manufacturers are encouraged to continuously moni-
Observed Result minus Predicted Value. E456
tor and improve upon their operations to enhance product
3.1.10 uncertainty, n—an indication of the variability asso-
quality.
ciated with a measured value that takes into account two major
components of error: (1) bias, and (2) the random error 4.4 Process Understanding for the Whole Process:
attributedtotheimprecisionofthemeasurementprocess. E456 4.4.1 For each product, process understanding covers the
process from the initial design of the chemical or biological
drug substance through manufacturing of the unit dose or
4. Process Understanding
device to final packaging. In addition, the critical quality
4.1 From physical, chemical, biological, and microbiologi-
attributes of the raw materials will in turn become inputs to the
cal perspectives, a process is considered to be well understood
drug product manufacturing process, as will process param-
when:
eters.
(1) All significant sources of variability in process inputs
4.4.2 Fig.1schematicallyillustratesthattheperformanceof
are identified and explained,
anyprocessoutput(Y)isafunctionoftheinputs(X),whichcan
(2) The effect of these sources of variability on product
be classified into one of six categories (that is, operator,
quality attributes can be accurately and reliably estimated
equipment, measurements, methods, materials, and environ-
based on the inputs to the process, and
mental conditions).
(3) Significant process parameters are continuously man-
4.4.3 Comprehensive understanding of the relationships of
aged and controlled to ensure that the process must produce
the process inputs and operating parameters to quality attri-
product which is continuously within required specifications to
butes of the resulting product is fundamental to developing a
the user specified required degree or confidence.
successful risk mitigation or control strategy, or both. Identi-
4.2 Awell-controlled process is a process where the risk of
fication of critical process parameters (CPPs) and critical raw
producing product not meeting required specifications is below
material attributes should be carried out using suitable experi-
the maximum acceptable level of risk as predetermined by the
mentalandinvestigativetechniques.Anunderstandingofthese
user.Accordingly, process understanding requires the compre-
critical inputs (CPPs and critical raw material attributes), and
hension and recall of process knowledge sufficient for the
their monitoring and control, is essential when designing a
logical, statistical, or scientific understanding, or combination
process that is able to consistently and reliably deliver product
thereof,ofhowsignificantprocessparametersandrawmaterial
of the desired quality.
attributes relate to, or impact the quality attributes of, the
4.4.4 One method for achieving the desired state is through
product being produced. Sufficient process understanding
multivariate analysis and control. The acceptable operating
should be achieved to reduce risk to an acceptable level for the
range of the critical inputs defines the relationship between the
patient, manufacturer, or any other stakeholder.
design space, control strategy and operating range(s).
4.4.5 Note that for raw materials, an additional source of
4.3 ALifecycle Commitment (Development and Commercial
variability derives from the potential for adulteration. This
Manufacture):
requires that manufacturers understand their incoming supply
4.3.1 Process understanding is fundamental to QbD. It is
chain and suppliers quality systems, and include methods to
important to realize that due to commercial realities (for
detect adulteration of materials in addition to confirming
example, finite resources, time, and money), a process will
identity as necessary, bearing in mind that adulteration may be
typically be commissioned as soon as the degree of process
difficult to detect by standard methods. It also requires that
understanding is sufficient to permit operation of the process
manufacturers use suppliers that are aware of these concerns
with an acceptably low, user specified, level of risk of
and are prepared to implement their own precautionary
producing out of specification product. While it may be
measures, and to permit transparency into their respective
appropriate to commission a process once this minimum
supply sources.
degree of process understanding is achieved, the risk that the
4.5 Tools of Process Understanding:
process may transition out of control steadily increases over
time (for example, process drift), and could exceed the 4.5.1 Process understanding begins with process design
maximum acceptable risk without warning, unless an ongoing (Practice E2474) and usually a structured, small scale devel-
program to enhance process understanding is in place. opment program which focuses on efficiently delivering a
E2475 − 10
FIG. 1 Input, Process, and Output Diagram
product meeting the required specifications. Tools that may be 5. Process Knowledge
applied during development and after commercialization in-
5.1 Process knowledge is the cornerstone of process under-
clude:
standing. There are various levels of process knowledge, and
(1) Scientific theory,
these are listed from lowest to highest state of understanding:
(2) Prior knowledge,
(1) Descriptive knowledge (what is occurring?),
(3) Design of experiments,
(2) Correlative knowledge (what correlations are empiri-
(4) Simulation of unit operations,
cally observed?),
(5) Selection of a suitable technology platform,
(3) Causal knowledge (empirical, what causes what?),
(6) Mathematical models,
(4) Mechanistic knowledge (explanations for observed
(7) Empirical/statistical models,
causality), and
(8) Appropriate instrumentation, and
(5) First principles knowledge (underlying physical,
(9) Appropriate analytical methods.
chemical, and biological phenomena of the mechanistic expla-
4.5.2 The measurement technologies include but are not
nations).
limited to spectroscopic, acoustic, or other rapid sensor tech-
5.2 Process knowledge is the accumulated facts about the
nologies. The development of these and other advanced tech-
process.Thisaccumulatedknowledgeisgenerallyembodiedin
niqueswillcontinuetoenableorenhancepredictivecontrolfor
a model of the process. Accordingly, process model is often
commercial pharmaceutical processes.
used synonymously with process knowledge.
4.5.3 The ability to measure process parameters and quality
5.3 Process understanding is demonstrated by the extent to
attributes inline, online, or atline in real time can contribute to
which process knowledge can be used to predict and control
process understanding and the ability to control the process.
the process outcomes; a well understood process will combine
These technologies offer the development scientist, commer-
knowledge from various sources to ensure a well controlled
cial production engineer and manufacturing personnel the
process and consistent product quality.
opportunity for additional insight. This is achieved through the
increased measurement frequency and availability of more 5.4 At any point in time for any manufacturing process, the
comprehensive data. level of understanding will likely be a combination of various
E2475 − 10
levels of understanding. As more knowledge is obtained 5.12 Periodic evaluation and re-validation (Practice E2617)
throughout the lifecycle of a product, the relative contribution of models should be conducted throughout a product’s life-
to understanding of the various levels is likely to change. cycle. This is true from research and development phases and
throughout commercialization of a product, where additional
5.5 Priorknowledgeisanyknowledgethatmaybeavailable
data (for example, non-conformances, investigations) from
through previous experience. Prior knowledge may come from
multiplemanufacturinglotsandalargepatientbasecanleadto
a number of sources including scientific literature, company
further understanding and improved control. Models should be
experience from research and development, and existing com-
periodically re-evaluated, revised, or re-validated as appropri-
mercial products such as lab and manufacturing investigations.
ate.
All knowledge that is available should be considered and
placed in context in order to optimize the overall lev
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