Quality, safety and regulatory · Stability and quality
“The mass balance in our stress study doesn't close, and we don't know where the missing part went.”
Forced degradation study: degradation products and mass balance
A stress study under ICH Q1A(R2) should show how an API degrades and whether your method captures every degradation product. CovaSyn predicts likely degradation pathways from structure, assigns observed masses and checks the mass balance. You receive a report that your analytical team reviews and signs off.
Starting point
When you need this
- After stress, assay plus degradation products adds up to well below 100 percent.
- Peaks appear in the chromatogram of the stressed sample whose structure nobody knows.
- A stress study has to be planned for a new substance, and conditions and target degradation are open.
- An authority or a sponsor asks whether your method is stability-indicating.
Result
What you get
Predicted degradation pathways
Likely degradation products under hydrolysis, oxidation, photolysis and heat, with mass and the functional group that reacts.
Mass balance check
Assay and degradation products reconciled, with the usual causes of gaps such as differing response factors and volatile or undetectable products.
Study design under ICH Q1A(R2)
Stress conditions, sampling points and a sensible target degradation, typically in the range of 5 to 20 percent, so the study stays meaningful.
Toxicological classification
Structural alerts for the degradation products and a preliminary ICH M7 assessment, so you know which peaks need particular attention.
Three ways
Yourself, together, or done for you
Run it yourself
Draw the molecule in the sketcher or use the tools through the CovaSyn MCP directly in Claude, ChatGPT or Cursor.
Go to MCPLearn it together
In a workshop your team learns how to answer questions like this with AI, cleanly and traceably.
See workshopsDone for you
We run the evaluation with our tools and deliver the finished report. Your expert reviews and signs off.
See Done-for-You
CovaSyn
The tools behind it
Deterministic calculations instead of guessed answers: the same tools we use for Done-for-You work are available to you directly.
Covams
Stress study planning, degradation product prediction, assignment of measured masses and mass balance calculation.
Covastab
Evaluation of stress data across conditions, with degradation rates and comparison of samples.
Covatox
Structural alerts and ICH M7 assessment for every proposed degradation product, with an applicability domain check.
Audience
Who it is for
For analytical, QC and CMC teams at contract labs, CDMOs and generics manufacturers who plan, evaluate or justify stress studies to sponsors and authorities.
What the computation does not replace
- Predictions do not replace measurement. A structure only counts as confirmed once MS fragments, retention time or a reference standard support it.
- A mass balance gap can be narrowed down, but not always closed from existing data. Often a second detector or a response factor from your lab is needed.
- The ICH M7 classification is a model-based preliminary assessment and does not replace review by your toxicologist.
Insights
Read on
Forced Degradation Study Design (ICH Q1A R2)
Forced degradation study design under ICH Q1A(R2): stressor choice, target degradation, mass balance and stability-indicating methods, with real tool output.
Read articleMass Balance in Forced Degradation, and Why It Fails
Why mass balance in forced degradation rarely closes: non-chromophoric and volatile degradants, adsorption and response factors, plus how to close the gap.
Read articleUnknown Impurity Identification by LC-MS/MS
Unknown impurity identification by LC-MS: formula from accurate mass, RDBE, isotope pattern and MS/MS fragment logic, with real CovaMS tool output and its.
Read articleICH M7 Classification: Class 1 to 5, by Example
ICH M7 classification explained class by class, with the dual (Q)SAR assessment and five real impurities scored live by CovaTox, including NDMA.
Read articleSignificant Change Under ICH Q1A: What Triggers It
Significant change ICH Q1A explained: the exact assay, degradant, dissolution and physical triggers, and what intermediate testing you owe once it fires.
Read article
Questions
Common questions
What to do when the mass balance in forced degradation doesn't close?
First check whether the degradation products have a different response factor than the API, whether volatile or non-UV-active products form and whether something stays on the column. CovaSyn predicts from structure which products are likely and shows which of them your method might miss. That turns a gap into a targeted follow-up measurement.
How do I design a stress study under ICH Q1A(R2)?
Typical conditions are acid and base hydrolysis, oxidation, heat, humidity and light under ICH Q1B, with a target degradation of about 5 to 20 percent. Excessive stress creates secondary products that never occur under real conditions. CovaSyn proposes conditions that match the reactive groups in your molecule.
How can I predict degradation products?
From the structure you can derive which groups hydrolyse, oxidise or react under light, and which masses result. CovaSyn builds that list and matches it against your measured masses, so unknown peaks get a structure proposal faster.
Do degradation products need an ICH M7 assessment?
Degradation products that actually occur or are expected in stability studies belong in the ICH M7 assessment. CovaSyn screens every proposed degradation product for structural alerts and provides a preliminary assessment that your toxicologist confirms or rejects.
Who can evaluate our forced degradation study for us?
CovaSyn does this as Done-for-You: you describe substance and data in the intro call, we agree on scope, and you typically receive the report within 5 working days once we have your data. Handled confidentially from the start.
Can I predict degradation products myself?
Yes. In the sketcher you draw the molecule and see core data instantly; the tools for degradation, mass balance and ICH M7 are available through the CovaSyn MCP directly in your AI assistant.
Quality, safety and regulatory
Related problems we solve
Next step
Tell us about your stress study.
30 minutes on Microsoft Teams with the CovaSyn team. If it is not a fit, we will say so.