WHO 发布 TRS 1067 附录 2，提出药品连续制造考虑要点
TRS 1067 - Annex 2: WHO points to consider in continuous manufacturing of pharmaceutical products
WHO 发布 TRS 1067 附录 2，提出药品连续制造的考虑要点。文件分章列出效益与挑战、良好实践、风险管理、控制策略、工艺动态、计算机化系统、验证与确认及稳定性试验等内容，并说明应与 ICH Q13 和 WHO GMP 一并阅读。文中示例以口服固体制剂为主，指出相关原则可延伸至其他剂型、生物制品和疫苗。
文件围绕连续制造列出风险管理、控制策略、工艺动态与验证等要点，并以口服固体制剂示例说明适用范围。
WHO 正式技術報告附錄：TRS 1067 - Annex 2: WHO points to consider in continuous manufacturing of pharmaceutical products
官方目錄發布日：2026-06-09（原文 9 June 2026）；報告年份、會議日期及適用範圍請以文件正文為準。
官方出版頁：https://www.who.int/publications/m/item/trs-1067---annex-2--who-points-to-consider-in-continuous-manufacturing-of-pharmaceutical-products
PDF 文字版；图形和原始排版请参阅官方 PDF。
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Annex 2
WHO points to consider in continuous manufacturing of
pharmaceutical products
For any further information or request, please send an email to the Norms and
Standards for Pharmaceuticals (NSP) Team at WHO, at email [email protected].
Contents
1. Introduction 96
2. Glossary 97
3. Benefits of and challenges in continuous manufacturing 98
3.1 Technical and operational challenges 99
3.2 Regulatory challenges 100
3.3 Workforce challenges 100
4. Good practice considerations 100
5. Risk management 101
6. Control strategy 102
7. Process dynamics 104
8. Computerized systems 105
9. Validation and verification 105
10. Stability testing 105
References 106
Further reading 106
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1. Introduction
Manufacturers of active pharmaceutical ingredients (APIs), excipients and
finished pharmaceutical products (FPPs) have predominantly used batch
processing as a means to manufacture their products.
In recent years, several manufacturers have opted to introduce continuous
manufacturing (CM) in pharmaceutical production. Although CM is a relatively
new approach in pharmaceutical product manufacturing, this concept has
been used in other industries for nearly a century. There are several examples
of industries utilizing this approach, including oil refining, metal smelting,
petrochemical product manufacturing, and certain excipient, food and beverage
manufacturing.
CM (including flow chemistry, where appropriate) can be applied to the
production of certain chemicals, starting materials (excipients and APIs) and FPPs.
CM requires automated systems, such as metering of input materials (at a
minimum), to ensure a sustainable and controlled manufacturing process.
In a CM process, the input materials are continuously fed into and
transformed within the process, and the processed output materials are
continuously removed from the system. This description can be applied to an
individual unit operation or the entire manufacturing process consisting of a
series of unit operations.
CM does not have to be end-to-end in production of a product. It could
be applied to some (semicontinuous) or all unit operations in a manufacturing
process. As an example, in the production of oral solid dosage forms, some steps
(such as feeding and mixing) or all steps can be included in CM.
Although the amount of material being processed at any given instance
may be relatively small in a CM process, the process can run over a period of
time to generate desired quantities of finished material meeting the necessary
WHO Technical Report Series, No. 1067, 2026
quality standard.
In the traditional batch manufacturing process, sampling and testing of
samples after certain processing steps are the norm. This often leads to down
times and hold times. The relatively new approach of CM, utilizing sensors for in-
line and on-line analytical testing, may reduce such down and hold times. It may
further facilitate utilizing the full capacity of equipment and production lines,
reduce human error, and support quality control and testing.
This document presents points to consider for manufacturers
implementing CM in the production of APIs and FPPs. Although the examples
given in the document focus on oral solid dosage forms, the principles may be
applied to other dosage forms, biologicals (such as therapeutic proteins) and
vaccines (for example, those manufactured by novel technology). This document
complements the International Council for Harmonisation of Technical
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Requirements for Pharmaceuticals for Human Use (ICH) Q13 harmonised
guideline Continuous manufacturing of drug substances and drug products (1) and
should be read alongside ICH Q13 and WHO good manufacturing practices.
2. Glossary
at-line. A system whereby samples are collected manually and the analyser is
located next to the process.
batch. A specific quantity of material produced in a process or series of processes
so that it is expected to be homogeneous within specified limits. In the case of
continuous production, a batch may correspond to a defined fraction of the
production. The batch size can be defined either by a fixed quantity or by the
amount produced in a fixed time interval.
batch size. The specified quantity of input material; or the quantity of output
material or product; or the time it takes to manufacture the specified quantity of
output material or product; or a combination of the above.
continuous manufacturing. Continuous feeding of input materials into a
process with processed output materials continuously removed from the system,
consisting of two or more integrated unit operations.
flow chemistry. Flow chemistry is also known as continuous flow or plug flow
chemistry; it involves a chemical reaction run in a continuous flow stream rather
than a batch production.
in-line. A process analytical technology system that is incorporated into the flow
of the process and produces continuous data without sampling using capacitance,
light scattering, spectroscopy, on-line liquid chromatography and other types of
sensors.
on-line. A system that is connected directly to the process and collects and
automatically analyses samples, which are never returned to the process.
pharmaceutical product. Any material or product intended for human or
veterinary use presented in its finished dosage form or as a starting material for
use in such a dosage form, that is subject to control by pharmaceutical legislation
in the exporting or importing state.
process analytical technology. A mechanism to design, analyse and control
manufacturing processes through the measurement of quality attributes of
intermediates or products and monitoring of process parameters that affect the
critical quality attributes.
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process control. The practice of monitoring and adjusting a process to achieve
a desired outcome. It is a combination of engineering and statistics that involves
using algorithms, mechanisms and architectures to maintain the output of a
process within a specific range.
process dynamics. The response of a manufacturing process to changing inputs,
conditions or transient events. A transient event is a temporary condition in
which a process goes through a dynamic change. This change may be due to
a disturbance or an intentional alteration in the selected operating conditions
(for example, start-up, shutdown or changes from one operating condition to
another).
quality by design. A systematic approach to development that begins with
predefined objectives and emphasizes product and process understanding and
process control, based on sound science and quality risk management.
real-time release testing. The ability to evaluate and ensure the quality of in-
process or final product based on process data, which typically include a valid
combination of measured material attributes and process controls.
residence time distribution. A measure of the range of residence times
experienced by material passing through a specific process environment, vessel
or unit operation.
state of control. A condition in which the set of controls consistently provides
assurance of continued process performance and product quality.
For other definitions, see the WHO Quality Assurance of Medicines
Terminology Database: https://www.who.int/publications/m/item/quality-
assurance-of-medicines-terminology-database.
WHO Technical Report Series, No. 1067, 2026
3. Benefits of and challenges in continuous manufacturing
The benefits and challenges of CM have been described in various guidelines and
articles (see “further reading” section).
CM may result in increased output of product in a shorter time frame
than traditional batch processing. It may also provide safety benefits due to lower
exposure risk to operators.
CM may, in certain cases, support economic and environmental
sustainability. Consideration should be given to environmental impact, water
and energy consumption, and evaluation of capital and operating costs.
CM may also present challenges to manufacturers. These include
providing specialized training of personnel in the new concept, managing
product changeover and cleaning of such lines.
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With the technical, operational and economic challenges, as well as
the risks associated with CM, it is important that manufacturers wanting to
move from batch manufacturing to CM processes ensure that there is sufficient
process knowledge to facilitate risk management and the development and
implementation of an appropriate control strategy. Ingredient and process
knowledge, through education and characterization, is needed to ensure an
appropriate control strategy if transitioning from batch to continuous operations.
Challenges to adopting CM in the pharmaceutical industry include:
■ technological issues (for example, process knowledge);
■ logistical concerns (for example, new equipment and computerized
systems);
■ advanced control strategies comprising complex analytical
instrumentation and technology for improved process control using
robust and reliable methods (for example, in-line, on-line and at-
line analytics);
■ real-time data strategies for critical quality attributes and critical
process parameters (for example, to maintain a state of control);
■ regulatory uncertainty (for example, different regulatory
requirements in countries);
■ integrating downstream unit operations (for example,
semicontinuous manufacturing);
■ personnel (for example, specific training and qualification);
■ risks (including actual and perceived risks);
■ economic issues (for example, return on investment);
■ flexibility issues (for example, adjusting process).
Batch-to-batch variability and purity for clinical applications is still one
of the biggest challenges with implementation (that is, continuous processing to
meet current good manufacturing practices and good laboratory practices).
3.1 Technical and operational challenges
The lack of commercially available equipment suitable for small-scale CM
lines presents a challenge to formulation and development facilities as well as
commercial manufacturers.
The importance of the link between batches produced and used during
clinical trials and commercial batches should also not be underestimated.
Operators should have knowledge of the complexities relating to
process control and associated risks due to equipment, sensor or computerized
system failure, leading to a lack of continuous material flow, overfilling,
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overpressurization, spills and backflow of material. Hence, operators should be
well trained and qualified.
3.2 Regulatory challenges
Furthermore, while CM aligns strongly with international guidelines, such as those
of the United States Food and Drug Administration and the ICH, pharmaceutical
manufacturing is a global enterprise, and companies must gain approval for
their products in multiple countries with their own regulatory bodies. Not all
regulatory agencies may have established requirements and standards for CM.
When changing from an existing batch manufacturing process to a
CM process, the continuous process can be introduced as a new process for a
new product or as a post-approval manufacturing change. Where required,
comparable quality and bioequivalence should be demonstrated (see also ICH
Q13 (1) risks, change and training).
More work and harmonization may be required to resolve issues related
to regulatory challenges and requirements of CM.
3.3 Workforce challenges
Designing, implementing and adequately regulating new approaches
in manufacturing require personnel who are skilled and well trained in
manufacturing as well as in the regulatory environment.
Additional training may be required for personnel in production,
quality control, quality assurance, engineering and the regulatory function, as
specialized equipment, sensors, feedback systems, computerized systems and
data management may be required in CM.
4. Good practice considerations
WHO Technical Report Series, No. 1067, 2026
Good practice considerations in CM should start at the product and process
development stage.
CM may require manufacturers to acquire new equipment; implement new
ways of managing existing equipment; acquire new instruments, computerized
systems and software; and establish new modes of operation. This may further
include a move to apply process analytical technology and principles of quality
by design.
The premises and equipment should be appropriate to support CM.
Equipment should remain within operating specifications over the duration of
the CM process.
The pharmaceutical quality system should be suitably designed and
appropriately implemented and maintained (2), including through material and
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process management; qualification and validation; and maintenance, calibration
and monitoring. Other pharmaceutical quality system elements include risk
management, process capability index, process performance index, managing
deviations, managing incidents and non-conformities (including material
diversion and disturbance), product stability, and a control strategy.
Raw and starting materials used in a product should be traceable and
consistently meet predefined specifications. As multiple lots of raw materials may
be introduced at various times in CM, traceability is essential. This will require
understanding of residence time distribution and process dynamics.
Systems should be in place for product collection, control and diversion
of non-conforming material, and product rejections. Understanding of residence
time distribution and process dynamics is required.
Other systems to be considered include:
■ detailed start-up and shutdown procedures;
■ how production collection and in-process sampling will occur as a
means of assuring continued process performance and product quality;
■ process validation and continued process verification procedures;
■ personnel training procedures;
■ cleaning and cleaning validation.
Appropriate resources should be provided.
Process models can be used for development of a CM process or
optimization of process parameters to establish state of control, diversion strategy,
material traceability and process dynamics.
Process parameters (including their settings and real-time data) should
be controlled and monitored as part of the control strategy.
5. Risk management
Risk identification, risk and harm assessment, risk control and risk communication
should be integral parts of the pharmaceutical quality system where CM is
employed (3, 4).
Quantitative or qualitative analysis using an appropriate tool – for
example, failure mode and effects analysis or a risk matrix – may be considered
when doing risk assessment.
Risk assessment should be done at various stages in the life cycle of a
product, from development through transfer of technology to commercial CM.
Risks relating to the sourcing and control of material, equipment,
processing steps and cleaning, as a minimum, need to be included in the
assessment. Each processing step or unit operation should be mapped out
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indicating, as appropriate, quality attributes and process parameters. Risks and
harms can then be assessed and controls identified.
Consideration should be given to:
■ input material attributes, including their impact on process
operations and product quality (note: process performance may
vary where input material attributes are not consistent – flowability,
particle size and distribution, cohesion, hygroscopicity and other
attributes should be considered in the selection of material, and the
manufacturer of the materials should be qualified as part of vendor
qualification);
■ process steps, including operating parameter settings (for example,
time, temperature, rotation per minute, amperage, speed, and
pressure during sifting, milling, blending, granulation, drying,
compression, filling, sealing and coating);
■ unexpected disturbances, possible deviations and non-
conformances (for example, poor material flow, vibration, product
build-up and material diversion).
The performance of computerized systems and the risks and impact
associated with failure of such systems should be considered.
Appropriate means should be identified for the detection and handling of
non-conforming material.
Risk assessment should be thorough to provide assurance that the
required controls are identified and are effective to ensure that a state of control
is achieved.
6. Control strategy
WHO Technical Report Series, No. 1067, 2026
The control strategy for CM in commercial production should be initiated during
the developmental phase of pharmaceutical products.
The control strategy should be based on the outcome of the risk assessment.
The control strategy should be clearly defined and describe all steps to
ensure that the state of control is achieved. Relevant elements include input
materials, residence time distribution, process dynamics, process monitoring,
material diversion, real-time release testing (if applicable), specifications and
process equipment.
The control strategy should have the ability to detect process departures,
thereby enabling timely corrective actions to be taken to bring the process back
into conformance.
Achieving and maintaining a state of control require appropriate
measures to be taken relating to the management of raw and starting materials;
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specifications; traceability; process monitoring; sampling; intermediates;
equipment; and product collection and rejection.
Mechanisms should be in place to identify any drift in parameters or data
trend that may be of concern. The root cause should be identified for significant
transient events to ensure that appropriate action is taken.
In addition to traceability, it may be necessary to have additional controls
when multiple lots of a raw material are used during CM.
Maintaining a state of control should provide assurance of consistent and
desired product quality.
In ensuring that the manufacturing process is in a state of control, at least
the following aspects should be considered and clearly defined:
■ start-up, pauses and shutdown;
■ in-process monitoring and control, with material collection and
diversion of non-conforming materials;
■ critical process parameters and critical quality attributes at various
stages in the process.
Flowcharts indicating processing steps, continuous and semicontinuous
steps and clear indication of location of sensors and probes may be useful.
The appropriate means of monitoring the process should be implemented.
Sampling should be defined. This includes a clear description of the number of
samples; frequency of sampling; sample size; sample location; in-line, on-line,
off-line or at-line sampling; and limits and acceptance criteria.
The objectives of sampling, collecting and processing data should be
clear, as data may be used in statistical analysis and trending. Set points and
control limits should be appropriate. It may be possible to apply new approaches
in technology and methodology in CM. CM affords more flexible handling
compared to traditional batch manufacturing. Process parameters may be
adjusted during processing based on measuring and results of quality attributes of
the intermediate or in-process material, in real time, using (for example) process
analytical technology. In-line sensors and devices may be useful to enable real-
time identification of departures from expected results.
Validated systems should be in place to manage diversion of potentially
non-conforming materials.
Based on process knowledge and understanding, the elements of a control
strategy for CM include:
■ measuring process parameters and critical quality attributes in a
timely manner;
■ maintaining the process in a state of control;
■ maintaining the product attributes within specifications;
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■ appropriate use of artificial intelligence;
■ optimizing process operation;
■ realization process operation;
■ realizing process efficiency improvements.
7. Process dynamics
Scientific knowledge supported by experimental data of the process dynamics
and variables are needed to ensure that CM processes are appropriately designed,
managed and operated within a state of control. Knowledge is required of the
differences that may exist between developmental batch and commercial batch
processing.
Processing steps in CM need to be well controlled to ensure the
production of uniform products and thus require different approaches in process
parameter control and monitoring. As an example, fluctuation in feed of raw
material may impact the quality of a blend. For improved monitoring and control
of the processing parameters, manufacturers may have to consider specifically
designed equipment and instrumentation, computerized systems, and feedback
systems. The selection of equipment and instrumentation should be suitable
for its intended purpose and process for semicontinuous and continuous
manufacturing, as applicable.
To obtain meaningful results, consideration should be given to:
■ instrument selection and suitability for process conditions;
■ analytical procedures and their development to ensure accuracy and
robustness;
■ sensor and probe placement for representative data collection;
WHO Technical Report Series, No. 1067, 2026
■ critical process parameters (such as flow rate, particle size
distribution, compression force), including maintenance, servicing
and calibration;
■ system performance (including accuracy, operating range and
sensitivity);
■ data integrity and compliance with good practice requirements,
including computerized system validation;
■ sampling strategy (method, location, frequency, representativeness
and sample size);
■ consistency in analysis across the expected concentration range;
■ acceptance criteria aligned with product quality attributes and
regulatory expectations.
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8. Computerized systems
Computerized systems should be appropriate for their intended use.
Computerized systems should be appropriately validated and be able to
ensure the integrity of data (5, 6).
9. Validation and verification
The principles of process validation, as described in WHO guidelines, should
be considered (7). In addition, specific attention should be given to start-up and
shutdown of the process, process run time evaluation, and the ability to detect
process excursions. Examples may include process robustness, process flow rate
and residence time.
In CM, careful consideration should be given to the manner in which
process performance and quality attributes are consistently controlled by the
control strategy.
Process monitoring is dependent on residence time distribution. Real-
time data collection and analysis during sampling should be representative of the
process to ensure that transients outside the state of control are detected.
Where a traditional approach in process validation is followed,
consideration should be given to the number of batches required for process
validation. Any variation in results of attributes between different batches should
be within an acceptable range. Consideration should be given to the possible
impact on the process capability where differences in quantities and times
(resulting in different batch sizes) in different batches are employed in CM.
10. Stability testing
Stability data for products manufactured by means of CM should be available.
The same principles for stability testing apply as outlined in WHO guidelines for
stability testing (8).
The selection of batches and the number of batches of product that should
be subjected to stability testing should be justified.
Consideration should be given to variables that may be impacting the
batches, such as the number of batches of input material to the batch of product
and batch size.
Unless otherwise justified, stability data from commercial batches
should be available and derived from batches where the state of control has been
demonstrated.
Consideration should be given to the impact on stability of changes in
such elements as run time, scale-out and process flow rate.
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References
1. Continuous manufacturing of drug substances and drug products. ICH Harmonized Guideline
Q13. Geneva: International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use; 2022 (https://database.ich.org/sites/default/files/ICH_Q13_
Step4_Guideline_2022_1116.pdf).
2. WHO good manufacturing practices for pharmaceutical products: main principles. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: forty-eighth report (Annex 2).
Geneva: World Health Organization; 2014 (WHO Technical Report Series No. 986; https://iris.who.
int/handle/10665/112733).
3. WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-seventh report (Annex 2). Geneva: World Health Organization;
2013 (WHO Technical Report Series No. 981; https://iris.who.int/handle/10665/81144).
4. Quality risk management. ICH harmonized guideline Q9 (R1). Geneva: International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; 2023 (https://
www.ich.org/page/quality-guidelines).
5. Good manufacturing practices: guidelines on validation. Appendix 5: Validation of computerized
systems. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third
report (Annex 3). Geneva: World Health Organization; 2019 (WHO Technical Report Series No.
1019; https://iris.who.int/handle/10665/312316).
6. Guideline on data integrity. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations: fifty-fifth report (Annex 4). Geneva: World Health Organization; 2021 (WHO Technical
Report Series No. 1033; https://iris.who.int/handle/10665/340323).
7. Good manufacturing practices: guidelines on validation. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: fifty-third report (Annex 3). Geneva: World
Health Organization; 2019 (WHO Technical Report Series No. 1019; https://iris.who.int/
handle/10665/312316).
8. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-second report
(Annex 10). Geneva: World Health Organization; 2018 (WHO Technical Report Series No. 1010;
https://iris.who.int/handle/10665/272452).
WHO Technical Report Series, No. 1067, 2026
Further reading
■ Burange AS, Osman SM, Luque R (2022). Understanding flow chemistry for the production of
active pharmaceutical ingredients. Iscience. 25(3).
■ Burcham CL, Florence AJ, Johnson MD (2018). Continuous manufacturing in pharmaceutical
process development and manufacturing. Annu Rev Chem Biomol Eng. 9(1):253–81.
■ Gamp I (2008). 5: A risk-based approach to compliant GXP computerized systems. Tampa, Florida:
ISPE.
■ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) (2005). Pharmaceutical development. ICH harmonized guideline Q8 (R2).
Geneva (https://www.ich.org/page/quality-guidelines).
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■ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) (2008). Pharmaceutical quality system. ICH harmonized guideline Q10. Geneva
(https://www.ich.org/page/quality-guidelines).
■ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human
Use (ICH) (2012). Development and manufacture of drug substances. ICH harmonized guideline
Q11. Geneva (https://www.ich.org/page/quality-guidelines).
■ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) (2014). Lifecycle management. ICH harmonized guideline Q12. Geneva (https://
www.ich.org/page/quality-guidelines).
■ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human
Use (ICH) (2022). Continuous manufacturing of drug substances. ICH harmonized guideline Q13.
Geneva (https://www.ich.org/page/quality-guidelines).
■ Matsuda Y (2018). PMDA/JP perspectives on continuous manufacturing (https://www.pmda.
go.jp/files/000241270.pdf).
■ Nasr MM, Krumme M, Matsuda Y, Trout BL, Badman C, Mascia S et al. (2017). Regulatory perspectives
on continuous pharmaceutical manufacturing: moving from theory to practice: September
26–27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals. J
Pharm Sci. 106(11):3199–206.
■ National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies;
Board on Chemical Sciences and Technology (2019). Continuous manufacturing for the
modernization of pharmaceutical production: proceedings of a workshop. Washington (DC):
National Academies Press.
■ Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017). The hitchhiker’s guide to flow chemistry.
Chem Rev. 117(18):11796–893.
■ United States Pharmacopeia (USP) (2022). Pharmaceutical continuous manufacturing: what drug
makers need to know. Rockville, MD.
■ United States Pharmacopeia (USP) (2023). Pharmaceutical continuous manufacturing: a guide
to control strategies for solid oral dose drugs. Rockville, MD (https://www.usp.org/supply-chain/
pharmaceutical-continuous-manufacturing-usp-technical-guide).
■ United States Pharmacopeia (USP) (2023). Technical guide: process modelling for advanced
manufacturing technologies (AMT). Rockville, MD.
■ United States Pharmacopeia (USP) (2024). Technical guide: in-vitro dissolution modeling for oral
solid drug product continuous manufacturing. Rockville, MD.
■ United States Pharmacopeia (USP) (2025). Control strategy for continuous manufacturing of drug
substances. Rockville, MD.
■ Wegner J, Ceylan S, Kirschning A (2011). Ten key issues in modern flow chemistry. Chem Commun.
47(16):4583–92.
■ World Health Organization (2024). Multisource (generic) pharmaceutical products: guidelines
on registration requirements to establish interchangeability. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: fifty-seventh report (Annex 8). Geneva (WHO
Technical Report Series No. 1052; https://iris.who.int/handle/10665/376607).
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