Quality by Design & Pharmaceutical Development
Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, founded on sound science and quality risk management. Articulated across ICH Q8, Q9 and Q10, it reframes quality as something designed into a product — not inspected into it at the end of the line.
What an explainer is not
A topic explainer is SPEQ’s synthesis of what a practice involves, cited to the standards that govern it. It does not reproduce their text, and it does not determine which of them apply to your product or process.
[ POSITION IN THE FRAMEWORK ]
7 DIMENSIONS · 25 LINKSQuality by Design bridges development and manufacturing across the GMP and quality-system disciplines: understanding built in early phases becomes the control strategy that the PAT, MES, and continuous-manufacturing systems execute.
06 · QUALITY MATURITY — QUALITY BY DESIGN & PHARMACEUTICAL DEVELOPMENT, REACTIVE TO ADAPTIVE
Development is empirical; quality is tested in at release, and parameter ranges cannot be defended from understanding.
A QTPP and CQAs are named, but the link from CPPs to CQAs is asserted rather than demonstrated.
CQA/CPP relationships are established by designed experiments and converge on a documented control strategy.
An approved design space gives operating flexibility; movement within it is managed without new regulatory filings.
Process models and PAT sustain real-time control; development knowledge continuously refines the control strategy.
SPEQ’s shared five-stage progression, labelled synthesis — not the FDA QMM rating scale. Where does your organization sit? Score your quality system →
07 · REGULATORY & EVIDENCE
GOVERNING STANDARDS · 4
Derived from the 4 standards SPEQ maps to this subject, across 1 regulatory body: ICH.
RECORDS & OBJECTIVE EVIDENCE
- A Quality Target Product Profile for each product
- Criticality risk assessments identifying CQAs and CPPs
- Designed-experiment records supporting parameter ranges
- A control strategy traceable to development understanding
- Design space justification in the regulatory submission
COMMON INSPECTION FINDINGS
- Control strategy not traceable to any documented process understanding
- Parameter ranges set by convention with no criticality assessment
- Development reports unavailable at the commercial manufacturing site
- Design space claimed in the filing but its edges never verified
- Parameter changes made without assessing the impact on CQAs
Build quality in, don’t test it in
The old model tested quality at the end: make the batch, test a sample, release or reject. QbD inverts that. It starts from the Quality Target Product Profile (QTPP) — what the product must do for the patient — and works backwards to a process designed to deliver it every time. Testing then confirms a controlled process rather than substituting for one.
ICH Q8 (Pharmaceutical Development) is where this understanding is built and documented. The design space and control strategy it produces give room to adjust within validated limits without a new submission — and a science-based answer when a regulator asks why the process looks the way it does.
CQAs, CPPs, and the design space
Two definitions do the heavy lifting. A Critical Quality Attribute (CQA) is a property that must be controlled within a limit to ensure product quality; a Critical Process Parameter (CPP) is an input whose variability affects a CQA. QbD is, in essence, understanding which CPPs drive which CQAs, and by how much.
That understanding defines a design space: the multidimensional combination of inputs and parameters shown to assure quality. Working within the approved design space is not considered a change and does not trigger a post-approval regulatory filing — one of QbD’s most practical regulatory benefits, giving manufacturers room to adjust without re-approval.
The control strategy is the output
Process understanding is only useful if it becomes control. QbD converges on a control strategy — the planned set of controls, derived from product and process understanding, that assures process performance and product quality. It spans input material controls, process controls, in-process and release testing, and the monitoring that keeps the process inside its design space. This is the bridge from development to process validation.
QbD, risk management, and the quality system
ICH Q8 does not stand alone. Quality risk management (ICH Q9) is how you decide which attributes and parameters are critical and where to focus effort; the Pharmaceutical Quality System (ICH Q10) is what sustains the design and control strategy across the lifecycle. Together the three guidelines are the modern operating model for pharmaceutical quality — QbD is the development half of it.
WORKED EXAMPLE — SPEQ SYNTHESIS
A hypothetical development team is preparing a first commercial filing and is asked whether it is taking a quality-by-design approach. The team has a specification, a set of process parameters that produced acceptable batches, and no documented rationale linking the two.
Start from the patient, not from the process
The quality target product profile states what the product must do for the patient. Every attribute that follows is justified by reference to it, and a development programme that cannot state this is optimising against its own history rather than against a need.
Identify critical quality attributes and say why each is critical
Criticality is a judgement about impact on safety and efficacy, made and recorded. An attribute listed as critical because it is measured, or omitted because it has never failed, is the failure mode this step addresses.
Link process parameters to attributes with evidence, not with sequence
A parameter is critical because varying it moves an attribute — shown by experiment or by sound mechanistic argument. Parameters inherited from the first successful batch are conventions, and calling them critical does not make the link real.
Establish the ranges you can defend, and do not claim more
A design space is a claim about a region in which quality is assured, and it carries a regulatory commitment. Claiming one that the data does not cover is worse than not claiming one at all; a set of justified proven acceptable ranges is a legitimate and often better answer.
Build the control strategy from the links you established
Each critical attribute is assured by something specific: a parameter held, an input controlled, a test performed. The control strategy is the map of those assurances, and gaps in it are where the process is running on assumption.
Write the reasoning down while it is still known
The rationale is the deliverable. Reconstructing why a range was chosen, two years later and after staff change, produces a plausible account rather than a true one — and the difference shows under questioning.
A development record holding a product profile, justified critical attributes, evidenced parameter links, defensible ranges, a control strategy derived from them, and the reasoning captured contemporaneously. Whether the filing claims a design space is a regulatory strategy decision the organisation makes on this evidence.
WHAT WOULD CHANGE THIS
- A legacy product with decades of manufacturing history is approached from the opposite direction — the data exists and the rationale is reconstructed from it, with the limits of that reconstruction stated.
- If the product is a well-understood platform, prior knowledge legitimately substitutes for some experimentation, provided the platform claim itself is evidenced.
- A programme heading for an abbreviated pathway may have different filing expectations, and the depth of the documented rationale should follow the pathway rather than the ambition.
FREQUENTLY ASKED
What is Quality by Design (QbD)?
A systematic, science- and risk-based approach to pharmaceutical development that starts from predefined objectives (the Quality Target Product Profile) and emphasises product and process understanding and control — designing quality into the product rather than testing it in. It is described in ICH Q8.
What is a design space?
The multidimensional combination of input variables and process parameters demonstrated to provide assurance of quality. Working within an approved design space is not considered a change and does not require a post-approval regulatory filing — a key practical benefit of QbD.
What is the difference between a CQA and a CPP?
A Critical Quality Attribute (CQA) is a product property that must stay within limits to ensure quality (e.g. purity, dissolution). A Critical Process Parameter (CPP) is a process input whose variability affects a CQA. QbD is largely about understanding which CPPs drive which CQAs.
Is QbD mandatory?
QbD is an expectation and a framework (ICH Q8/Q9/Q10), not a single binding rule — a fully traditional development approach is still permitted. But regulators increasingly expect the process understanding QbD produces, and the design-space flexibility is only available if you do the QbD work.