1What ICH Q8(R2) covers.
ICH Q8(R2), Pharmaceutical Development, describes the suggested content of section 3.2.P.2 of a marketing application in the Common Technical Document format.¹ Part I, the parent guideline, reached Step 4 on 10 November 2005. Part II, the annex that describes the principles of quality by design, reached Step 4 on 13 November 2008. The current version, R2, corrected two figure titles in August 2009.¹ FDA published it as guidance in November 2009, and the EMA holds it as a scientific guideline.²³ It does not apply to submissions during clinical research, though Q8 says its principles are important to consider then as well.¹
Its premise is that “quality cannot be tested into products; i.e., quality should be built in by design.”¹ The annex is “not intended to establish new standards or to introduce new regulatory requirements”. An applicant can choose an empirical approach, a more systematic one, or a combination of both.¹
2The vocabulary of quality by design.
Q8(R2) defines quality by design as “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”. Its glossary defines the terms that follow from it.¹
| Term | What Q8(R2) means by it |
|---|---|
| Quality target product profile (QTPP) | A prospective summary of the quality characteristics a drug product should ideally achieve to ensure the desired quality, taking account of safety and efficacy. |
| Critical quality attribute (CQA) | A physical, chemical, biological or microbiological property that should be within an appropriate limit, range or distribution to ensure the desired product quality. |
| Critical process parameter (CPP) | A process parameter whose variability affects a CQA, so it should be monitored or controlled. |
| Design space | The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. |
| Proven acceptable range | A characterised range of one process parameter that, with other parameters held constant, produces material meeting the relevant quality criteria. |
| Control strategy | A planned set of controls, derived from product and process understanding, that ensures process performance and product quality. |
| Real time release testing | Evaluating and ensuring quality from process data, typically a valid combination of measured material attributes and process controls. |
At a minimum, development should define the QTPP, identify the product’s potential CQAs, determine the CQAs of the drug substance and excipients, select a manufacturing process and define a control strategy.¹ The enhanced, quality by design approach adds a systematic evaluation that identifies, through prior knowledge, experiments and risk assessment, which material attributes and process parameters affect product CQAs, and determines the functional relationships between them. That understanding is used with quality risk management to set the control strategy, which can include a design space or real time release testing.¹ Q8’s own illustration is a cross-functional team that builds an Ishikawa diagram, ranks the variables with FMEA and then studies the highest-ranked ones by design of experiments.¹
3Design space, and why it matters after approval.
The design space is proposed by the applicant and is subject to regulatory assessment and approval. “Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.”¹ It can be described as ranges or as more complex mathematical relationships, set for one unit operation or across the whole process, and developed at any scale, provided its relevance to the production-scale process is justified.¹ A combination of proven acceptable ranges does not constitute a design space, and determining the edge of failure is not essential to establishing one. Expanding, reducing or redefining an approved design space is subject to regional requirements.¹
Real time release testing can replace end-product testing, but “does not replace the review and quality control steps called for under GMP to release the batch”.¹
4Minimal and enhanced approaches compared.
Appendix 1 of Q8(R2) contrasts the two. It says current practice typically lies between them, and that the enhanced approach does not necessarily mean a design space or real time release testing.¹
| Aspect | Minimal approach | Enhanced, quality by design approach |
|---|---|---|
| Development | Mainly empirical, often one variable at a time | Systematic, with multivariate experiments relating material attributes and process parameters to CQAs |
| Manufacturing process | Fixed; validation based mainly on initial full-scale batches | Adjustable within the design space; a lifecycle approach to validation and, ideally, continuous process verification |
| Process controls | In-process tests mainly for go or no-go decisions; off-line analysis | PAT tools with feed-forward and feedback controls; operations tracked and trended |
| Specifications | The primary means of control, based on batch data at registration | Part of the overall control strategy, based on desired product performance |
| Control strategy | Mainly intermediate and end-product testing | Risk-based, with controls shifted upstream and the possibility of real time release testing |
| Lifecycle management | Reactive problem solving and corrective action | Preventive action and continual improvement |
The reward is regulatory flexibility, and Q8 ties it to knowledge rather than effort: “The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided in the registration application.” It is the knowledge gained and submitted, “and not the volume of data collected”, that forms the basis for science- and risk-based submissions.¹
5How Q8 connects to Q9, Q10, Q12 and Q14.
Q8 relies on quality risk management under ICH Q9 and a pharmaceutical quality system under ICH Q10. Where a company applies quality by design and quality risk management linked to an appropriate quality system, “opportunities arise to enhance science- and risk-based regulatory approaches”.¹
ICH Q12, adopted on 20 November 2019 and issued by FDA as guidance in May 2021, carries this into the commercial phase; it describes Q8(R2) and Q11 as focused mostly on development, registration and launch.⁴⁵ Q12 defines established conditions as “legally binding information considered necessary to assure product quality”, any change to which needs a submission to the regulator, and says an enhanced approach can focus them on the most important input parameters.⁴ ICH Q14, adopted on 1 November 2023, sets out minimal and enhanced approaches to analytical procedure development. Its enhanced approach records performance criteria in an analytical target profile and may define proven acceptable ranges or method operable design regions.⁶
6How it runs in Seal.
In Seal’s process development blueprint, experiments, actual execution and analytical evidence stay connected to a versioned process definition, and failed experiments remain part of the process evidence. Neil compares runs, identifies missing context and prepares the next experiment; scientists review the design and run the work. In process characterisation, each condition runs against the configured study protocol with its actual settings and results, proposed ranges are linked records that keep their basis when scientists approve them, and reviewed ranges connect to the operating protocol and PPQ requirements with the evidence behind them. Specialist DoE analysis can stay in JMP, Minitab, R or Python, connected to the study records.
For the dossier, CMC content keeps a reproducible connection to the protocols, execution records, analytical results, specifications and process definitions behind it. Where established conditions have been agreed, any change to them needs a submission, and regulatory owners determine the reporting route.
References
- 1ICH Q8(R2), Pharmaceutical Development, ICH, August 2009. https:/
/ database. ich. org/ sites/ default/ files/ Q8%28R2%29%20Guideline. pdf (read 6 November 2026) - 2Guidance for Industry, Q8(R2) Pharmaceutical Development, FDA, November 2009. https:/
/ www. fda. gov/ media/ 71535/ download (read 6 November 2026) - 3ICH Q8 (R2) Pharmaceutical development, Scientific guideline, EMA/
CHMP/ ICH/ 167068/ 2004, European Medicines Agency. https:/ / www. ema. europa. eu/ en/ scientific- guidelines/ ich- q8- r2- pharmaceutical- development (read 6 November 2026) - 4ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, ICH, 20 November 2019. https:/
/ database. ich. org/ sites/ default/ files/ Q12_ Guideline_ Step4_ 2019_ 1119. pdf (read 6 November 2026) - 5Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Guidance for Industry, FDA, May 2021. https:/
/ www. fda. gov/ regulatory- information/ search- fda- guidance- documents/ q12- technical- and- regulatory- considerations- pharmaceutical- product- lifecycle- management- guidance (read 6 November 2026) - 6ICH Q14, Analytical Procedure Development, ICH, 1 November 2023. https:/
/ database. ich. org/ sites/ default/ files/ ICH_ Q14_ Guideline_ 2023_ 1116. pdf (read 6 November 2026)
AQuestions and answers
Do FDA or the EMA require quality by design?
No. The Q8(R2) annex introduces no new regulatory requirements, and an applicant can develop a product empirically, systematically or with a mix of both. At a minimum, though, the aspects critical to product quality should be determined and the control strategy justified.
What is the difference between a design space and a proven acceptable range?
A proven acceptable range is tested for one parameter while the others are held constant. A design space describes how several inputs and parameters interact and still assure quality. Q8(R2) says a combination of proven acceptable ranges does not make a design space.
Do you need a design space to use quality by design?
No. Q8(R2) says the enhanced approach does not necessarily mean establishing a design space or using real time release testing. It notes that current industry practice typically lies somewhere between the minimal and enhanced approaches.
What is analytical quality by design?
It applies the same thinking to test methods. The ICH guideline for it is Q14, which does not use the phrase but describes an enhanced approach: an analytical target profile setting the performance the method needs, risk assessment and experiments on method parameters, and a control strategy that can include proven acceptable ranges or method operable design regions.
What are ICH Q12 established conditions?
The elements of the approved application that are legally binding because they are needed to assure product quality, so any change to them needs a submission to the regulator. Better product and process understanding can focus them on the parameters that matter most. Information that is not an established condition is supportive information, and changing it does not involve a regulatory communication. Unless a regional requirement says otherwise, identifying established conditions is not mandatory.
How does ICH Q8 relate to Q9 and Q10?
Q8’s annex says that where a company applies quality by design and quality risk management under ICH Q9, linked to a pharmaceutical quality system as described in ICH Q10, opportunities arise for more science- and risk-based regulatory approaches. In Q8’s own example of a risk assessment tool, a team lists variables on an Ishikawa diagram, ranks them with FMEA and then studies the highest-ranked by design of experiments.