ASTM E2968-14 关于连续生产的标准指南 Standard Guide for Application of Continuous Processing in the Pharmace

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Designation: E2968 −14
Standard Guide for
Application of Continuous Processing in the Pharmaceutical
Industry
1
This standard is issued under the ﬁxed designation E2968; 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
1.1 This guide introduces key concepts and principles to
assist in the appropriate selection, development and operation
of continuous processing technologies for the manufacture of
pharmaceutical products.
1.2 Particular consideration is given to the development and
application of the appropriate scientiﬁc understanding and
engineering principles that differentiate continuous manufac-
ture from traditional batch manufacturing.
1.3 Most of the underlying concepts and principles (for
example, process dynamics and process control) outlined in
this guide can be applied in both Drug Substance (DS) and
Drug Product (DP) processes. However it should be recognized
that in Drug Substance production the emphasis may be more
on chemical behavior and dynamics in a ﬂuid phase whereas
for drug product manufacture there may be a greater emphasis
on the physical behavior and dynamics in a solid/powder
format.
1.4 This guide is also intended to apply in both the devel-
opment of a new process, or the improvement/redesign of an
existing one.
1.5 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this
standard.
1.6 This standard does not purport to address all of the
safety concerns, if any, associated with its use. It is the
responsibility of the user of this standard to establish appro-
priate safety and health practices and determine the applica-
bility of regulatory limitations prior to use.
2. Referenced Documents
2.1 ASTM Standards:
2
E2363 Terminology Relating to Process Analytical Technol-
ogy in the Pharmaceutical Industry
E2475 Guide for Process Understanding Related to Pharma-
ceutical Manufacture and Control
E2537 Guide for Application of Continuous Quality Veriﬁ-
cation to Pharmaceutical and Biopharmaceutical Manu-
facturing
E2898 Guide for Risk-Based Validation of Analytical Meth-
ods for PAT Applications
2.2 FDA Documents:
3
FDA Guidance for Industry PAT A Framework for Innova-
tive Pharmaceutical Development, Manufacturing, and
Quality Assurance (2004)
3. Terminology
3.1 Deﬁnitions:
3.1.1 For general deﬁnitions, refer to Terminology E2363
and Guides E2537 and E2475.
3.2 Deﬁnitions of Terms Speciﬁc to This Standard:
3.2.1 back mixed process—a process with a residence time
distribution (RTD) which is non zero and potentially signiﬁcant
compared to the mean residence time.
3.2.1.1 Discussion—For example, in an idealized fully back
mixed process quantities of material will be mixed into a single
homogeneous condition such that a rapid step change in the
properties of inlet material will not result in an equivalent step
change in the properties of the output material but will be
reﬂected in a more gradual change. The rate of this change will
depend on the equipment characteristics, residence volume,
1
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
Subcommittee E55.01 on Process Understanding and PAT System Management,
Implementation and Practice.
Current edition approved Dec. 1, 2014. Published April 2015. DOI: 10.1520/
E2968-14.
2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Standards volume information, refer to the standard’s Document Summary page on
the ASTM website.
3
Available from Food and Drug Administration (FDA), 10903 New Hampshire
Ave., Silver Spring, MD 20993-0002, http://www.fda.gov.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the
Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
1
 
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and the residence time distribution/degree of mixing. A fully

back mixed process may be considered and modeled as one or

more continuously stirred tank reactors (CSTR).

3.2.2 controlled state—A process is in a controlled state

when it is: (1) Under Process Control, and (2) operating

normally, such that the measured critical quality attributes of

the product are within the deﬁned acceptable range.

3.2.3 dynamic process control system—an automated con-

trol system which monitors the condition of the product or the

process, or both, predicts or detects a change to the product

quality away from a target condition (that is, Setpoint), and

then changes the process conditions during processing in order

to maintain the product quality at the target value (or within the

speciﬁed range of target values). Depending on the dynamics

of the process the corrections may be applied immediately as a

step change or as a time dependent function (for example, a

ramp or exponential function). Such real time control systems

may include for example:

3.2.3.1 feedback control—a control strategy which is in-

tended to eliminate drift or deviation in a speciﬁc product

attribute away from the target (Setpoint) by means of:

(1) Measuring the attributes of material leaving a process

operation,

(2) Comparing the measured values with target (Setpoint)

values for the attributes, and

(3) Using a process model containing appropriate process

dynamics in order to calculate revised Setpoint values for the

relevant process conditions.

3.2.3.2 feed forward control—a control strategy which mea-

sures either: (1) speciﬁc critical attributes of materials as they

enter a speciﬁc process, or (2) other upstream factors (for

example, ﬂow rates, temperature, etc.), and uses this informa-

tion in combination with an appropriate process model to

adjust the Setpoint of the process conditions in order to reduce

the impact of the upstream change on the quality of the

material leaving the process step.

3.2.3.3 multivariate model based control—measurements of

one or more product attributes and process conditions are used

in a model of the process to determine the process conditions

required to achieve the correct product quality.

3.2.4 continuous process—a process where, during normal

operation, raw materials are continuously fed into the system at

the same time as acceptable product is continuously removed

from the system.

3.2.4.1 Discussion—(1) In a continuous process, the degree

of transformation of any speciﬁc quantity of material from an

initial condition into the subsequent condition is a function of

the process parameters applied and either:

(a) The position of the material as it ﬂows through the

process,

(b) The duration that the material has been within the

process, or

(2) A continuous process may be operated to transform a

pre-deﬁned quantity of material into a pre-deﬁned physical

quantity of product which is then subjected to a disposition

decision. The size of the resulting lot is predeﬁned by the

amount of starting material (with the option to divert certain

amount of material taken from online control), and this is

comparable to conventional discrete or batch manufacturing

operations.

(3) Alternatively a continuous process may be operated

with an ‘inﬁnite’ run-time, in which quantities of product are

deﬁned during the operation of the process in a ﬂexible way,

based on principles of science and risk (for example, as any

entity produced in a certain time, or containing a certain lot

of a starting material), and subjected to a disposition

decision.

(4) A process consisting of a series of interconnected unit

operations or transformations can be considered to be

continuous even if it also contains transformations of deﬁned

quantities of material which, when viewed at a particular

scale of scrutiny or level of detail, might be considered to be

composed of a sequence of individual discrete events.

(5) During periods of startup, shutdown or processing of

small quantities of material, or both (for example, for

development/experimental or clinical studies), it is possible

that not all unit operations within a continuous production

line will be in normal or steady state conditions at the same

time. For example: the ﬁrst unit operation could already be

shut down while the material is processed further in subse-

quent unit operations. This condition should not automati-

cally invalidate the deﬁnition of the process as representative

of normal continuous operation; however care must be taken

to understand the impact of this mode of operation on

product quality.

3.2.5 normal operation—behavior of the process which can

be expected or predicted, or both, based on an understanding of

the process. Unforced variability in the process or product

which can be expected, predicted and characterized statistically

or predictable variability, or both, which is forced by an

external stimulation may be considered as normal operation.

3.2.6 plug ﬂow process—a process with a residence time

distribution (RTD) which approaches zero.

3.2.6.1 Discussion—For example, in an idealized plug ﬂow

process a step change of the quantity, quality, or identity of the

input materials is, after a deﬁned time, directly and equally

reﬂected by a step change in the output.

3.2.7 process control setpoint—a process control Setpoint is

a speciﬁc target value for a process parameter or product

attribute which is used by a dynamic control system. The

dynamic process control system will determine what corrective

control action to apply in order to try to bring the speciﬁc

parameter or attribute closer to the Setpoint value.

3.2.7.1 Discussion—A Setpoint may be speciﬁed together

with upper and lower target values such that corrective control

action may be reduced once the value is within the target range.

A target range speciﬁed by upper and lower target values only

has no explicit speciﬁed Setpoint value and hence corrective

process control action is often suspended once the parameter or

attribute is within the target range.

E2968 − 14

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3.2.8 process disturbance—an un-requested and un-

controlled change in a measured or unmeasured parameter

which has the effect of changing the process conditions or

product quality (that is, a short-term transient condition).

3.2.9 process time constant—a measure of the rate at which

the process can change from steady state operation at one

condition to steady state operation at another condition.

3.2.10 quasi-steady state—conditions where some indi-

vidual process parameters are consistently varying in time but

with a set pattern of variation (for example, compression force

in a tablet press). In this guide, quasi-steady state conditions

are considered equivalent to steady state conditions.

3.2.11 recipe-based process control system—an automated

control system which maintains speciﬁc process parameters at

pre-speciﬁed ﬁxed values (that is, according to a predetermined

recipe) without adjustment of process parameters based on

either measurement and feedback of product quality attributes

or measurement and feed-forward of input material quality

attributes or upstream conditions.

3.2.12 steady state—consistent operation over a period of

time where all relevant process parameters and product quali-

ties are not subject to variation outside of a deﬁned range of

values.

3.2.12.1 Discussion—(1) A steady state condition by itself

does not directly imply that the deﬁned targets are correct with

respect to achieving acceptable product quality.

(2) Steady state implies only that the process is not subject

to signiﬁcant variance with respect to time.

(3) Achieving or maintaining acceptable product quality

may require an adjustment of target values and hence a

transition between two steady state conditions.

3.2.13 transient conditions—conditions where the process is

disturbed from steady state or is in transition between one

steady state condition to another (that is, the process conditions

or product quality are not in steady state or quasi-steady state).

Transients may be due to either external disturbances or

intentional changes in the selected operating conditions.

3.2.14 residence time—the time that process material is in a

speciﬁc process environment/vessel/unit operation.

3.2.15 residence time distribution (RTD)—a measure of the

range of residence times experienced by material passing

through a speciﬁc process environment/vessel/unit operation.

Hence in a process where the RTD is not zero a quantity of

material which all enters the process at the same time may

leave at different times and hence is not all resident in the

process for the same time. The RTD can be used to characterize

this difference in residence time and hence understand how

changes to the process or materials will propagate through the

process.

3.2.16 Under Process Control—behavior of the process

when it responds in a predictable way to the actions of the

control system and is able to achieve and maintain operation at

a speciﬁc process control Setpoint or Setpoints.

3.2.16.1 Discussion—Physical or chemical limitations may

prevent a process from responding to the process control

system (for example, control valve already wide open) and

hence under such conditions the process might be considered to

be not fully Under Process Control. In such a situation (for

example, transient conditions, start up and shutdown), the plant

may be considered to be Under Process Control if the Process

Control Setpoints are managed such that the process is not

constantly operated at its limits.

4. Signiﬁcance and Use

4.1 Although some continuous processing is used in the

pharmaceutical industry (for example, puriﬁed water

production, inherently continuous individual unit operations

such as dry granulation and compression), these operations are

generally operated in isolation and do not deliver the potential

beneﬁts of an integrated continuous manufacturing operation.

The FDA Guidance for Industry PAT document speciﬁcally

identiﬁes that the introduction of continuous processing may be

one of the outcomes from the adoption of a science-based

approach to process design.

4.2 This guide does not:

4.2.1 Suggest that continuous production is suitable for the

manufacture of all pharmaceutical products.

4.2.2 Provide guidance on issues related to the safe opera-

tion of a continuous process or continuous processing equip-

ment. It is the responsibility of the user of this standard to

establish appropriate health and safety practices and determine

the applicability of regulatory limitations prior to use.

4.2.3 Recommend particular designs or operating regimes

for continuous manufacturing.

4.3 Appendix X1 includes a table comparing the character-

istics of continuous and discrete or batch processes.

5. Operation of Continuous Manufacturing Systems

5.1 Operational Considerations:

5.1.1 In order to successfully introduce continuous

processing, due consideration should ﬁrst be given to the

overall operation and support of the system during the lifecycle

of the plant and product, for example:

5.1.1.1 Considerations for process and product develop-

ment:

(1) Flexibility of the system to produce small quantities of

material under different operating conditions during develop-

ment of product and process understanding, and

(2) Suitability for manufacture of variable quantities of

product at stable operating conditions for clinical trials sup-

plies.

5.1.1.2 For increasing process capacity from development

to commercial production, consider:

(1) Scale up of run length duration,

(2) Increase in production rate,

(3) Scale out by addition of parallel processing lines, and

(4) A risk based approach to scale up of continuous

process.

5.1.1.3 For stable manufacturing operations over the target

run length, consider:

(1) Ability of the system to produce consistent product

over the intended duration of the operation,

(2) Mechanisms of failure and degradation of performance

together with robust methods of detection,

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Designation:E2968−14StandardGuideforApplicationofContinuousProcessinginthePharmaceuticalIndustry1ThisstandardisissuedundertheﬁxeddesignationE2968;thenumberimmediatelyfollowingthedesignationindicatestheyearoforiginaladoptionor,inthecaseofrevision,theyearoflastrevision.Anumberinparenthesesindicatesthe...

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