Quality by design and control strategy ICH guidance U.S. regulations Proposed practice
Quality by design starts from the quality a product must have, traces it to the materials and process parameters that move it, and builds the controls that hold it
The ICH chain from target profile to lifecycle, applied to four botanical product types and linked to the hazard analysis U.S. food rules require. Product tables are proposed starting points.
Related: a 3D design space with a reliability slider · scale-up and tech transfer
4ICH guidelines in one chain: Q8(R2), Q9(R1), Q10, Q12
4botanical product types with proposed target profiles and CQA tables
8long-term stability pull points for a 36-month claim under ICH Q1A(R2)
2.6–18×range of 25 °C shelf lives one 6-month accelerated result can imply
Status. EUTECNIQ has no products, processes or data; everything below is a proposal. ICH guidelines are written for drugs and serve here as good practice beside 21 CFR Part 111.
The ICH chain
Four ICH guidelines form one chain: product knowledge in Q8(R2), risk in Q9(R1), the quality system in Q10 and change in Q12
From target profile to lifecycle, and the guideline that governs each linkICH Q8(R2), Q9(R1), Q10, Q12
Definitions in the guidelines' own words, with a botanical reading of each
Explanation, details and sources
A quality target product profile (QTPP) summarizes the quality the product should have. Attributes that must stay within limits become critical quality attributes (CQAs); risk assessment links them to the inputs that move them, and the control strategy holds those inputs.
| Term | Definition (quoted) | Source | For a botanical extract (EUTECNIQ reading) |
|---|---|---|---|
| Quality target product profile (QTPP) | "A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product." | ICH Q8(R2) glossary | Identity, strength (marker content), contaminant limits, physical form, stability and packaging, written before development starts. |
| Critical quality attribute (CQA) | "A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality." | ICH Q8(R2) glossary | Marker content, fingerprint, residual solvent, water activity, microbial counts, elemental contaminants. |
| Critical process parameter (CPP) | "A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality." | ICH Q8(R2) glossary | Extraction temperature and solvent composition; evaporator temperature; dryer outlet temperature. |
| Critical material attribute (CMA) | "A physical, chemical, biological, or microbiological property or characteristic of an input material" that "should be within an appropriate limit, range, or distribution to ensure the desired quality of that drug substance, excipient, or in-process material." | Yu LX et al., AAPS J 2014 (authors including FDA scientists); not an ICH glossary term | Species and plant part, marker content and contaminant load of each raw lot, milled particle size. |
| Design space | "The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality." | ICH Q8(R2) glossary | For a drug, proposed by the applicant and approved by the regulator. Supplements have no such filing; a demonstrated region still documents why set points are where they are (see design space and optimization). |
| Proven acceptable range | "A characterised range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria." | ICH Q8(R2) glossary; Part II, section 2.4.5 | One-factor ranges. Q8(R2) states that a combination of proven acceptable ranges does not constitute a design space. |
| Control strategy | "A planned set of controls, derived from current product and process understanding that ensures process performance and product quality." | ICH Q10 (quoted in the Q8(R2) glossary) | Raw-material specifications and identity tests, set-point ranges, in-process checks, release tests and the stability program. |
| Process analytical technology (PAT) | "A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality." | ICH Q8(R2) glossary; FDA PAT guidance (2004) | For example, near-infrared measurement of marker content during extraction. |
| Real time release testing | "The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls." | ICH Q8(R2) glossary | A long-term goal; it requires validated models and is not planned for early operations. |
| Risk | "The combination of the probability of occurrence of harm and the severity of that harm." | ICH Q9(R1) glossary (from ISO/IEC Guide 51:2014) | Applied to consumers: an adulterated or contaminated lot reaching the market. |
| Established conditions | "Legally binding information considered necessary to assure product quality." | ICH Q12, section 3.2.1 | Applies to drug marketing applications only. Supplements have no marketing authorization, so there are no established conditions. |
Four product types
Each product type has its own critical attributes, measured by named compendial methods and held at a specific step of the process
For a standardized dry extract, each critical attribute is held at a named stepProposed control points
Dry extract: identity and marker content lead; a wrong raw lot cannot be fixed later
Show the table (5 rows)
| QTPP element | Proposed target | Why it is in the profile |
|---|---|---|
| Identity | Stated species and plant part; drug-to-extract ratio and extraction solvent declared | A supplement maker must test the identity of every dietary ingredient (21 CFR 111.75(a)(1)(i)) |
| Strength | Marker content within a stated range, set per product | Defines the dose the customer formulates with |
| Purity and contaminants | Limits for residual solvent, elemental contaminants, pesticides and microbes | Part 111 requires limits on contamination that may adulterate (111.70(b)(3) and (e)) |
| Physical form | Free-flowing powder with a stated particle size and bulk density | Blending and encapsulation downstream |
| Stability | Retest period supported by data in the commercial package | Marker loss and moisture uptake over time |
Show the table (7 rows)
| CQA | Why it is critical | How it is measured | Where it is controlled |
|---|---|---|---|
| Identity and fingerprint | Substitution and adulteration change the whole composition | USP ⟨563⟩ Identification of Articles of Botanical Origin; ⟨203⟩ HPTLC procedure; HPLC fingerprint | Raw-material receipt (identity test of each lot); release |
| Marker content | Sets the declared strength | HPLC (USP ⟨621⟩ Chromatography), validated per ICH Q2(R2) | Extraction set points; standardization with carrier; release |
| Residual solvent | Solvent left after evaporation and drying | USP ⟨467⟩ Residual Solvents (headspace GC) | Evaporator end point; dryer outlet temperature |
| Water and water activity | Microbial growth, caking and chemical change | USP ⟨921⟩ Water Determination; ⟨922⟩ Water Activity; ⟨731⟩ Loss on Drying | Dryer outlet temperature; moisture-barrier packaging |
| Elemental contaminants and pesticides | Carried in from soil, water and cultivation | USP ⟨2232⟩ Elemental Contaminants in Dietary Supplements (with ⟨233⟩ procedures); ⟨561⟩ Articles of Botanical Origin (pesticides) | Supplier qualification and raw-material testing |
| Microbial quality | Botanicals carry soil and plant microflora | USP ⟨2021⟩, ⟨2022⟩ and ⟨2023⟩ (nutritional and dietary supplements) | Raw-material limits; hold times; release |
| Particle size and density | Blend uniformity and capsule fill | USP ⟨429⟩ Light Diffraction Measurement of Particle Size; ⟨616⟩ Bulk Density and Tapped Density of Powders | Atomizer setting; feed solids |
Nanoemulsion: droplet size and its stability fail first
Show the table (5 rows)
| QTPP element | Proposed target | Why it is in the profile |
|---|---|---|
| Form and use | Oil-in-water liquid concentrate carrying a lipophilic extract, diluted into beverages | Disperses a poorly water-soluble active in water |
| Strength | Marker content per mL within a stated range | Dose per serving after dilution |
| Appearance after dilution | Stated clarity or turbidity, no visible separation | Customer acceptance; depends on droplet size |
| Physical and chemical stability | No creaming or separation and limited oxidation over the retest period | A nanoemulsion is not thermodynamically stable, so it separates over time (McClements 2012) |
| Microbial safety | Microbial limits met; preservation and pH system stated | Water-based product |
Show the table (6 rows)
| CQA | Why it is critical | How it is measured | Where it is controlled |
|---|---|---|---|
| Droplet size and polydispersity | Governs creaming rate, Ostwald ripening and appearance | USP ⟨430⟩ Particle Size Analysis by Dynamic Light Scattering | Homogenizer pressure and passes; emulsifier-to-oil ratio |
| Zeta potential | Electrostatic repulsion between droplets | Electrophoretic light scattering (ISO 13099-2) | Emulsifier choice; pH and ionic strength |
| Marker content | Declared strength | HPLC (USP ⟨621⟩), validated per ICH Q2(R2) | Formulation; release |
| Oxidation of the oil phase | Off-flavor and loss of oxidizable actives | Peroxide value (USP ⟨401⟩ Fats and Fixed Oils) | Nitrogen blanketing; antioxidants; temperature during homogenization |
| pH | Preservative efficacy and droplet charge | USP ⟨791⟩ pH | Formulation; in-process check |
| Microbial quality | Water-based product | USP ⟨2021⟩, ⟨2022⟩ and ⟨2023⟩ | Preservation system; hygienic filling; release |
- Small, stable droplets≠demonstrated bioavailability, which needs human pharmacokinetic data
Spray-dried powder: moisture and glass transition decide flow and protection
Show the table (4 rows)
| QTPP element | Proposed target | Why it is in the profile |
|---|---|---|
| Form | Free-flowing powder that disperses in water | Use in powders, tablets and beverages |
| Protection of the active | Most of the active inside the wall material, with little on the surface | Surface active oxidizes and degrades first |
| Strength | Active content within a stated range | Dose |
| Stability | No caking and limited loss over the retest period | Amorphous powders take up water and become sticky |
Show the table (6 rows)
| CQA | Why it is critical | How it is measured | Where it is controlled |
|---|---|---|---|
| Moisture and water activity | Lowers the glass transition temperature; supports microbial growth | USP ⟨921⟩; ⟨922⟩ | Outlet temperature; feed rate |
| Glass transition temperature | Above it, an amorphous powder becomes sticky and cakes | Differential scanning calorimetry (USP ⟨891⟩ Thermal Analysis) | Wall material; moisture |
| Encapsulation efficiency | Share of active protected inside the particle | Surface versus total active by solvent wash and HPLC (no compendial method; method to be validated) | Feed emulsion droplet size; solids; inlet temperature |
| Particle size, density and flow | Dosing and blending | USP ⟨429⟩; ⟨616⟩; ⟨1174⟩ Powder Flow | Atomization; feed solids |
| Physical state | Recrystallization changes dissolution and stability | X-ray powder diffraction (USP ⟨941⟩) | Formulation; storage humidity |
| Active content and residual solvent | Strength; solvent carried from the feed | HPLC (USP ⟨621⟩); USP ⟨467⟩ | Feed preparation; drying |
Capsule: Part 111 itself names the attributes
21 CFR 111.70(e) requires product specifications "for the identity, purity, strength, and composition of the finished batch of the dietary supplement, and for limits on those types of contamination that may adulterate."
Show the table (6 rows)
| CQA | Why it is critical | How it is measured | Where it is controlled |
|---|---|---|---|
| Identity of each dietary ingredient | Required for every lot of every dietary ingredient | At least one appropriate identity test per dietary-ingredient lot (111.75(a)(1)(i)); botanical methods as above | Component receipt |
| Strength per capsule | Label claim | Validated assay (HPLC, USP ⟨621⟩) | Blend uniformity; fill weight |
| Weight variation | Dose uniformity between capsules | USP ⟨2091⟩ Weight Variation of Dietary Supplements | In-process fill-weight checks |
| Disintegration | The capsule must open for its contents to dissolve | USP ⟨2040⟩ Disintegration and Dissolution of Dietary Supplements | Excipients; capsule shell; storage humidity |
| Contaminants | Adulteration limits | USP ⟨2232⟩; ⟨2021⟩–⟨2023⟩ | Component specifications; release |
| Water activity | Shell brittleness or softening; microbial growth | USP ⟨922⟩ | Room humidity; packaging |
USP general chapter titles as registered by USP (USP–NF DOI records, Crossref prefix 10.31003), checked October 23, 2026; 21 CFR 111.70 and 111.75 (eCFR, current as of October 21, 2026); ICH Q2(R2), adopted 1 November 2023; ISO 13099-2 (2025 edition replaces 2012). Targets are EUTECNIQ proposals.
Which compendial methods serve which product type: one chromatography chapter serves all fourFrom the proposed CQA tables
Data table: methods by product type
| Method | Product types (number of CQAs) |
|---|---|
| The table fills in from the four CQA tables when the page's scripts run; the tables above list every method. | |
USP ⟨621⟩ chromatography appears in all four CQA lists; the water-activity (⟨922⟩) and microbial (⟨2021⟩, ⟨2023⟩) chapters each serve three.
Explanation, details and sources
A proposed QTPP and CQA list for four planned product types. Methods are USP general chapters or ICH guidelines; targets are placeholders each program would set from data.
Initial risk assessment
A cause-and-effect matrix ranks which inputs to study first; in this illustrative scoring, solvent composition and extraction temperature lead
Top-ranked input
Its score
Inputs with a 9 in this ranking
Process inputs × CQAs for a spray-dried standardized extractIllustrative scores Proposed
9 strong3 moderate1 weak0 none expectedCMA: critical material attribute candidate · CPP: critical process parameter candidate
| Input (type) | Identity and fingerprint weight 10 | Marker content weight 10 | Degradation products weight 7 | Residual solvent weight 8 | Water and water activity weight 6 | Particle size and flow weight 4 | Microbial quality weight 9 | Elemental and pesticide residues weight 9 | Weighted total |
|---|---|---|---|---|---|---|---|---|---|
| Botanical identity and plant part CMA | 9 | 3 | 0 | 0 | 0 | 0 | 1 | 3 | 156 |
| Marker content of the raw lot CMA | 3 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 120 |
| Contaminant load of the raw lot CMA | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 81 |
| Bioburden of the raw lot CMA | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 0 | 81 |
| Milled particle size CMA | 0 | 3 | 1 | 0 | 0 | 0 | 0 | 0 | 37 |
| Extraction temperature CPP | 3 | 9 | 9 | 0 | 0 | 0 | 1 | 0 | 192 |
| Extraction time CPP | 1 | 3 | 3 | 0 | 0 | 0 | 1 | 0 | 70 |
| Solvent composition (ethanol fraction) CPP | 9 | 9 | 1 | 1 | 0 | 0 | 0 | 1 | 204 |
| Solvent-to-solid ratio CPP | 0 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 38 |
| Evaporator temperature and vacuum CPP | 1 | 3 | 9 | 3 | 0 | 0 | 0 | 0 | 127 |
| Concentrate hold time CPP | 1 | 3 | 3 | 0 | 0 | 0 | 3 | 0 | 88 |
| Spray-dryer inlet temperature CPP | 0 | 1 | 3 | 3 | 3 | 3 | 1 | 0 | 94 |
| Spray-dryer outlet temperature CPP | 0 | 1 | 3 | 9 | 9 | 3 | 0 | 0 | 169 |
| Feed solids and feed rate CPP | 0 | 0 | 1 | 3 | 3 | 9 | 0 | 0 | 85 |
| Carrier ratio (e.g., maltodextrin) CPP | 0 | 9 | 0 | 0 | 3 | 3 | 0 | 0 | 120 |
Why the 9 scores are 9 (mechanisms)
- Identity and plant part → identity and fingerprint. A different species or part has a different set of constituents.
- Raw-lot marker content → marker content. Extraction recovers a fraction of what the plant contains.
- Contaminant load → elemental and pesticide residues. Extraction concentrates whatever is soluble; processing does not remove elements.
- Bioburden → microbial quality. Without a microbial-reduction step, counts track the raw material.
- Extraction temperature → marker content and degradation. Diffusion and solubility rise with temperature, and so do degradation rates (Arrhenius).
- Solvent composition → identity, fingerprint and marker content. Ethanol fraction sets which constituents dissolve; the design-space study shows marker-type responses peaking near 60% ethanol.
- Evaporator temperature → degradation. Time at temperature in the concentrate is the largest heat exposure.
- Dryer outlet temperature → residual solvent and water. The outlet temperature sets the final moisture and the driving force for solvent removal.
- Feed solids and rate → particle size. Droplet size from the atomizer scales with feed viscosity and solids.
- Carrier ratio → marker content. Adding carrier is how an extract is standardized down to its declared strength.
Explanation, details and sources
Each cell scores how strongly an input should move a CQA on the 0, 1, 3, 9 scale; weighted row totals rank the inputs. Scores are mechanism-based hypotheses that designed experiments then confirm or demote.
Ishikawa diagram
A fishbone sorts the causes of out-of-specification marker content into materials, process parameters and measurement before the first batch
Six cause categories for an out-of-specification marker result, tagged by typeProposed analysis
Explanation, details and sources
ICH Q8(R2) Appendix 2 describes the sequence: draw an Ishikawa diagram, rank the causes with FMEA or a similar tool, then test the high-ranked ones by designed experiments. The operational-excellence library uses the same tool after a failure.
HACCP and preventive controls
Food-safety hazards follow a parallel logic: HACCP's seven principles and its decision tree find the steps where control is essential
FAO and WHO. General Principles of Food Hygiene, CXC 1-1969 (adopted 1969; revised 1997, 2003, 2020, 2022), sections 17 and 19; English text read in the FAO/WHO/Japan Food Hygiene Association bilingual edition. Definitions: a critical control point is "a step at which a control measure or control measures, essential to control a significant hazard, is/are applied in a HACCP system."
The decision tree asks four questions at each step where a significant hazard is identified
Choose a worked example or answer the questions.
About the worked examples
Choose a worked example or answer the questions yourself. The examples are illustrative teaching judgments, not a hazard analysis of a real process.
Q1. Can the significant hazard be controlled to an acceptable level at this step by prerequisite programs (e.g. GHPs)?
Codex example CCP decision tree, with the current path highlightedCodex text
Codex footnotes: at Q1, consider the likelihood and severity of the hazard and whether prerequisite programs suffice; if no CCP is found at Q2 to Q4, modify the process or product and repeat the hazard analysis; at Q4, if a control at this step works together with one at another step, both steps should be considered CCPs.FAO and WHO. CXC 1-1969, revised 2022, Annex IV, Figure 1 (example CCP decision tree); questions and outcomes quoted. Codex states that other tools can be used if the requirements of Step 7 are met.
Explanation, details and sources
The Codex General Principles of Food Hygiene (CXC 1-1969, revised 2022) apply seven HACCP principles in a 12-step sequence:
| Step | Task (Codex wording) | HACCP principle |
|---|---|---|
| 1 | Assemble HACCP team and identify scope | Preliminary step |
| 2 | Describe product | Preliminary step |
| 3 | Identify intended use and users | Preliminary step |
| 4 | Construct flow diagram | Preliminary step |
| 5 | On-site confirmation of flow diagram | Preliminary step |
| 6 | List all potential hazards that are likely to occur and associated with each step, conduct a hazard analysis to identify the significant hazards, and consider any measures to control identified hazards | 1. Conduct a hazard analysis and identify control measures |
| 7 | Determine the critical control points | 2. Determine the critical control points (CCPs) |
| 8 | Establish validated critical limits for each CCP | 3. Establish validated critical limits |
| 9 | Establish a monitoring system for each CCP | 4. Establish a system to monitor control of CCPs |
| 10 | Establish corrective actions | 5. Establish the corrective actions to be taken when monitoring indicates a deviation from a critical limit at a CCP has occurred |
| 11 | Validation of the HACCP plan and verification procedures | 6. Validate the HACCP plan and then establish procedures for verification to confirm that the HACCP system is working as intended |
| 12 | Establish documentation and record keeping | 7. Establish documentation concerning all procedures and records appropriate to these principles and their application |
U.S. law: Part 111 for supplements, Part 117 for dietary ingredients
In U.S. law, finished supplements follow Part 111 and dietary-ingredient manufacture generally follows Part 117, whose preventive controls include but are not limited to CCPs.
Part 117's hazard-analysis and preventive-control subparts do not apply to supplement operations that comply with Part 111; the exemption does not cover dietary ingredients sold to other manufacturers.
The two rules use related but distinct terms:
| Topic | 21 CFR Part 111 (dietary supplements) | 21 CFR Part 117 (human food, incl. dietary ingredients) |
|---|---|---|
| Who is covered | Anyone who manufactures, packages, labels or holds a dietary supplement (111.1(a)) | Food facilities. Subparts C and G do not apply to supplement operations "in compliance with the requirements of part 111" and FD&C Act section 761 (117.5(e)) |
| Where control is required | Specifications "for any point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement" (111.70(a)) | Preventive controls for each "hazard requiring a preventive control" found by a written hazard analysis (117.130, 117.135) |
| Hazard identification | Through specifications for identity, purity, strength, composition and contaminant limits (111.70(b), (e)) | Biological, chemical (including radiological) and physical hazards that occur naturally, are introduced unintentionally, or are introduced "for purposes of economic gain" (117.130(b)) |
| Types of control | Component, in-process and finished-batch specifications; identity testing; master and batch records | Process, food allergen, sanitation and supply-chain controls, a recall plan and other controls; controls at CCPs "if there are any CCPs" (117.135) |
| CCP definition | Not used | "A point, step, or procedure in a food process at which control can be applied and is essential to prevent or eliminate a food safety hazard or reduce such hazard to an acceptable level" (117.3) |
| Validation | Tests and examinations must be "appropriate, scientifically valid methods" (111.75(h)(1)) | Preventive controls must be validated as capable of controlling the hazards (117.160) |
| EUTECNIQ proposal | Finished-supplement operations under Part 111 | Ingredient-only operations under Part 117, with a written food safety plan; HACCP tools used inside it |
Questions for counsel Needs counsel
- Which program covers an extract sold to a customer who only encapsulates or labels it? FDA's compliance guide applies Part 111 to an ingredient supplier whose customer "simply packages" or labels it as a supplement.
- How should a site making both bulk extracts and finished supplements divide its Part 111 and Part 117 programs and records?
- Which supplier-verification duties apply to imported botanicals (Foreign Supplier Verification Program, 21 CFR Part 1 Subpart L)?
- Does any Part 117 exemption or modified requirement apply at the planned scale?
No counsel opinions have been obtained yet; not legal advice. More on the two rules: quality system.
eCFR, 21 CFR 111.1, 111.70, 111.75; 21 CFR 117.3, 117.5(e), 117.130, 117.135, 117.160 (current as of October 21, 2026); FDA, Small Entity Compliance Guide for the dietary supplement CGMP rule (citing 72 FR 34752 at 34791); 80 FR 55908 (September 17, 2015).
Process analytical technology
Measuring quality during processing lets a plant adjust the batch in progress; published studies show near-infrared models can track constituents during extraction
At-line, on-line and in-line differ in where the sample goesFDA guidance definitions
Text version of the three definitions
- At-line: "the sample is removed, isolated from, and analyzed in close proximity to the process stream."
- On-line: "the sample is diverted from the manufacturing process, and may be returned to the process stream."
- In-line: "the sample is not removed from the process stream and can be invasive or noninvasive."
FDA. Guidance for Industry: PAT, a Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (September 2004), section IV; Pan X et al. Sensors. 2015;15(4):8749–8763; Delueg S et al. Molecules. 2019;24(13):2480. Proposed uses are EUTECNIQ plans, not installed equipment.
Explanation, details and sources
FDA's PAT framework (September 2004) groups the tools in four categories and distinguishes three measurement locations. A measurement "need not be absolute values of the attribute of interest."
The four tool categories, a published botanical example of each, and the proposed use:
| PAT tool category (FDA) | Published botanical example | Proposed EUTECNIQ use |
|---|---|---|
| Process analyzers | On-line NIR at pilot-scale extraction of Fructus aurantii, calibrated against HPLC for naringin, hesperidin and neohesperidin; ensemble PLS lowered prediction error (Pan et al. 2015). At-line NIR during maceration of rosemary leaves in 70% ethanol; test-set R² 0.93 to 0.96 for three reference assays (Delueg et al. 2019). | NIR or UV at the extraction end point; UV switching at the resin-column cut point |
| Multivariate tools for design, data acquisition and analysis | Partial least squares calibration of spectra to reference assays (both studies above) | Designed experiments and PLS models, validated before use for decisions |
| Process control tools | Not shown in these studies | Dryer outlet temperature held by feed-rate trim; evaporator end point by density or refractive index |
| Continuous improvement and knowledge management tools | Not shown in these studies | Trending of CPPs and CQAs across lots (see control charts) |
Control strategy
Control strategies range from extensive end-product testing to real-time engineering control, and a new botanical process would start at the testing end
A new botanical process would start at level 3 and climb only with dataProposed starting point
Text version: the three levels, quoted, and what each would mean for a botanical extract
| Level | Description (quoted) | What it would mean for a botanical extract |
|---|---|---|
| Level 3 | "The level of control traditionally used in the pharmaceutical industry. This control strategy relies on extensive end-product testing and tightly constrained material attributes" and process parameters. | Fixed set points, full release testing of every lot. The proposed starting point. |
| Level 2 | "Pharmaceutical control with reduced end-product testing and flexible material attributes and process parameters within the established design space." | Extraction time adjusted to raw-lot marker content within a demonstrated region; reduced testing justified by data. |
| Level 1 | "Automatic engineering control to monitor the CQAs of the output materials in real time." | PAT-based end points and real-time release; a long-term option that needs validated models. |
Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, Woodcock J. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–783; ICH Q8(R2) Part II, section 2.5. The botanical column is EUTECNIQ's proposal.
Explanation, details and sources
Yu and co-authors, including FDA scientists, described three levels of control. Moving up a level replaces end-product testing with process understanding, which has to be earned with data.
Stability as a CQA
A 6-month accelerated result implies a 25 °C shelf life 2.6 to 18 times the 40 °C life, depending on activation energy
ICH Q1A(R2), Step 4, 6 February 2003, section 2.1.7.1; ICH Q1E, Step 4, 6 February 2003. A consolidated revision of ICH Q1 reached Step 2 in April 2025; ICH's Q1 work plan of February 2026 anticipated Step 4 in November 2026. FDA, Small Entity Compliance Guide (Part 111), section IX, citing 72 FR 34752 at 34855.
First-order loss with Arrhenius temperature dependencek(T) = k40 exp[ −EaR(1T − 1313.15 K) ]
t90 = ln(10/9)k(T), k40 = −ln(1 − loss)6 months
t90 = ln(10/9)k(T), k40 = −ln(1 − loss)6 months
Rate constant at 40 °C
t90 at 40 °C
t90 at the storage temperature
25 °C, if Ea = 50 kJ/mol
25 °C, if Ea = 150 kJ/mol
Lowest Ea giving the target at 25 °C
Predicted time to 90% of the initial marker content, by storage temperature and activation energyIllustrative model
Vertical axis is logarithmic. Amber marks combinations predicted to reach the target shelf life. Points mark the ICH long-term conditions at the chosen activation energy.
Show data (predicted t₉₀ in months)
| Ea (kJ/mol) | 15 °C | 20 °C | 25 °C | 30 °C | 35 °C | 40 °C |
|---|---|---|---|---|---|---|
| The table fills in when the page's scripts run; the equations give every value. | ||||||
Educational model with invented inputs; not a shelf-life assignment. A real program measures loss at several temperatures and humidities, checks that one mechanism holds, and confirms with long-term data at the labeled condition.Arrhenius equation (IUPAC Gold Book, "Arrhenius equation"); ICH Q1A(R2) storage conditions; ICH Q1E section 2.3 on extrapolation.
Method, assumptions and limits
- What it calculates
- The first-order rate constant implied by a stated loss after 6 months at 40 °C, the rate at other temperatures for an assumed activation energy, and the time to 90% of the initial content (t90).
- Equations
- k40 = −ln(1 − f)/6 per month; k(T) = k40 exp[−(Ea/R)(1/T − 1/313.15)]; t90 = ln(10/9)/k; lowest Ea for a target t* at 25 °C: Ea = R ln(t*k40/ln(10/9)) / (1/298.15 − 1/313.15).
- Variables and units
- f fraction lost; T in kelvin; R = 8.314462618 J/(mol·K); Ea in kJ/mol; times in months.
- Assumptions
- Single first-order pathway; Arrhenius behavior from 15 to 40 °C; no humidity, oxygen or light effect; no change of physical state. One mechanism at every temperature; humidity ignored (40 °C/75% RH is also more humid than 25 °C/60% RH, which the model does not separate); activation energy is an input, not known until measured at several temperatures.
- Valid range
- Loss 1–25% at 40 °C; Ea 50–150 kJ/mol; 15–40 °C. The range of activation energies is illustrative, chosen to show sensitivity.
- What it does not establish
- A shelf life, a retest period or an expiration date. For drugs, ICH Q1E caps extrapolation and requires confirmation with long-term data.
- Verification
- Independent Python reference in
tests/numerics/ref/platform-qbd-control-strategy.py, which integrates the rate law numerically to the 90% point.
ICH Q1E caps extrapolation, so 12 months of real-time data support at most 24 months for a drug
Choose what the data show and the months of long-term data.
Scope of the cap
The cap applies to room-temperature drug products; supplements have no federal equivalent.
Longest retest period or shelf life that may be proposed
Of which extrapolated beyond the data
Arrhenius projection at 25 °C (model above)
No significant change at the accelerated condition; little or no change and variability: up to twice, but not more than 12 months beyond, the long-term period (2.4.1.1).
ICH Q1E, sections 2.4.1 and 2.4.2 (room-temperature storage). Supporting data and statistical conditions apply as stated in the guideline.
Explanation, details and sources
ICH Q1A(R2) sets the storage conditions; ICH Q1E limits extrapolation beyond real-time data, and the model above shows why. Supplements have no federal expiration-date requirement, but FDA says a firm "should have data to support any such date that you place on a product label."
| Study (general case) | Storage condition | Minimum period covered by data at submission |
|---|---|---|
| Long term | 25 °C ± 2 °C / 60% RH ± 5% RH, or 30 °C ± 2 °C / 65% RH ± 5% RH | 12 months |
| Intermediate | 30 °C ± 2 °C / 65% RH ± 5% RH (none if 30 °C/65% RH is the long-term condition) | 6 months |
| Accelerated | 40 °C ± 2 °C / 75% RH ± 5% RH | 6 months |
The Arrhenius model is also used on the science lab page (time course of an accelerated study) and drying and particle engineering (moisture and powder stability).
Stability protocol
ICH Q1A(R2) tests stability every 3 months in year one, every 6 in year two, then yearly through the shelf life
Storage conditions and their tolerances, general case and refrigerated productsICH guidance (drugs)
Long-term pull points8
All pull points11
Test occasions, 3 primary batches33
Minimum pull points by storage conditionICH guidance (drugs)
ICH Q1A(R2) sections 2.1.6 and 2.2.6 (testing frequency) and 2.2.3 (at least three primary batches).
Method, assumptions and limits
- What it calculates
- The minimum time points ICH Q1A(R2) recommends for a proposed shelf life of at least 12 months, and the test occasions for three primary batches.
- Rules
- Long term: every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. Accelerated: at least three time points including the initial and final (e.g., 0, 3 and 6 months) from a 6-month study. Intermediate, when called for by a significant change at the accelerated condition: at least four time points (e.g., 0, 6, 9, 12 months) from a 12-month study. Refrigerated products: long term 5 °C ± 3 °C, accelerated 25 °C ± 2 °C/60% RH ± 5% RH, no intermediate condition.
- Valid range
- Shelf lives of 12 to 60 months in whole years. Reduced designs (bracketing, matrixing) and extra points near expected significant change are not modeled.
- Does not establish
- A shelf life or a regulatory obligation for supplements: Part 111 does not require an expiration date, though FDA expects data behind any date on a label. A consolidated revision of ICH Q1 is in progress (Step 2 April 2025).
- Verification
- Unit tests in tests/unit/qbd.test.js; independent reference cases in tests/numerics/ref/platform-qbd-control-strategy.py.
A 36-month claim needs 8 long-term pull points, and every point is tested on at least three primary batches.
Lifecycle
After launch, the quality system keeps the process in its demonstrated region and routes every change through review
Four Q10 elements keep the process in its region; Q12 tools stay with drugsICH Q10 (2008), Q12 (2019)
Text version of the ICH Q10 elements and ICH Q12 tools
ICH Q10 elements
- Process performance and product quality monitoring system
- Corrective action and preventive action (CAPA) system
- Change management system
- Management review of process performance and product quality
Enablers: knowledge management and quality risk management.
ICH Q10, 2008ICH Q12 tools
- Established conditions: "legally binding information considered necessary to assure product quality"
- Post-approval change management protocol (PACMP)
- Product lifecycle management (PLCM) document
A change to an established condition needs a submission to the regulator.
ICH Q12, 2019Explanation, details and sources
ICH Q10 names four elements and two enablers. ICH Q12's change tools apply to drug marketing applications; for supplements EUTECNIQ proposes written change control as good practice.
Scale-up rules, FDA's three process-validation stages and ICH Q10 technology transfer are on Scale-up and tech transfer.
Build the quality case for a botanical product
EUTECNIQ would answer a product concept with a proposed QTPP, CQA list, risk assessment and test plan.