Active Substances and Excipients Flashcards
Informed of change in API manufacturing process from 5 step to 4 step – what are my concerns?
a. Impurities concerns – guidance. Classifications of impurities (residual solvents and elemental)
b. I discussed catalysts, impact on the API (polymorphism etc) discussion with med info.
You are informed that the API manufacturing process has changed from a 5-step to a 4-step process. What are your concerns?
My primary concern is the potential impact on the quality of the API — specifically the impurity profile, residual solvents, elemental impurities, and physical properties such as polymorphism.
A reduction in synthetic steps could eliminate critical purification or reaction stages, which might lead to elevated levels of impurities, or the introduction of new ones.
As a QP, I would not certify a batch until I am assured that the new route has been fully evaluated through change control, and I have access to updated regulatory and analytical data demonstrating equivalence or superiority to the previous route.
What do you expect to change in the impurity profile?
The impurity profile might change significantly. The shortened synthesis could remove intermediate steps that eliminated specific impurities — this could result in either increased levels of known impurities or the appearance of new, route-specific impurities.
Also, depending on the reagents or solvents introduced, residual solvent levels could shift. Therefore, a thorough comparative impurity assessment should be conducted between the old and new routes.
What guidelines do you refer to for impurities?
would refer to the ICH Q3A(R2) for impurities in new drug substances, Q3C for residual solvents, and Q3D for elemental impurities.
If there is a potential for genotoxic impurities, ICH M7 would be relevant.
Also, Q6A helps define specifications, and Q11 covers the development of drug substances, including control of impurities
How would you assess the risk from residual solvents?
I would expect the API manufacturer to provide a residual solvent risk assessment in line with ICH Q3C.
They should demonstrate that Class 1 solvents (carcinogenic) are avoided unless justified; Class 2 solvents (toxic) are within permitted daily exposure (PDE); and Class 3 solvents are within 5000 ppm.
Analytical validation should confirm compliance with these limits.
What about elemental impurities?
Elemental impurities could be introduced through catalysts or reagents.
I’d expect a risk-based evaluation in accordance with ICH Q3D, addressing Class 1, 2A, 2B, and 3 elements.
I’d review data on potential sources, their control in the process, and confirm via analytical results — typically ICP-MS — that levels are below PDE thresholds
If the process introduces new catalysts, what do you do?
I’d want to understand the nature of the catalyst — is it metal-based, what class it falls under in ICH Q3D, and whether it is likely to carry through to the final API.
I’d require fate and purge data, showing that any residuals are removed to acceptable levels. If not, additional purification steps or tighter specifications may be needed.
Could this affect the polymorphic form of the API?
Yes, definitely. Polymorphism is often impacted by crystallisation conditions, solvents, temperature, or seeding — all of which could change in a revised route.
A new synthetic route could unintentionally generate a new or unstable polymorph, affecting solubility, bioavailability, and stability.
Why is polymorphism a concern for the QP?
Different polymorphs can have different solubility, dissolution rates, and stability profiles.
If the polymorphic form changes, the bioequivalence of the product could be affected, and dissolution specifications may no longer be appropriate.
I would expect XRPD or DSC data to confirm the same polymorphic form is produced as before.
You said you’d speak with Medical Information — why?
If there is a potential change in impurity profile or physical form, I would want to understand any impact on clinical safety or efficacy.
The Medical Information team or clinical safety group can provide insight into the toxicological relevance of new impurities or changes in exposure.
This is especially important if we are dealing with narrow therapeutic index drugs or high-risk patient populations.
Would this require a regulatory variation?
Yes, most likely. A change in the API manufacturing process is a registered detail in the dossier.
For a licensed product, this would normally require at least a Type II variation. For an IMP, the IMPD would need updating.
What data would you require from the API manufacturer?
- Updated process description and flow chart
- Risk assessments (e.g. impurity fate and purge studies)
- Analytical comparison of impurity profiles (old vs. new)
- Validation of critical process parameters
- Stability data (if any form or impurity change)
- Batch analysis results
- Confirmation of GMP compliance and regulatory approval (variation approval letter or updated ASMF/IMPD)
Can you give an overview of the key differences between small molecule API vs Biotech/biological API?
What are the differences in facility requirements and specific examples?
QP declaration?
Nitrosamines
Setting up new API supplier - How would you do that?
In depth conversation about API impurities, PDE, how would you control them, ICH Q1 and ICHQ3, method transfer.
API site address change; no change control; no MA variation. What would you do?
You’ve got a new blockbuster product and your team has told you that they are making some changes to the API: they have been able to reduce from 5 steps to 4 and are also changing to a different manufacturing site (same company but different address) and also scaling up – thoughts ?
Your site has got a new API for the manufacturing of a new product. What are your concerns.
What are the main synthesis and manufacturintem manage
g steps for a chemical API?
You receive an ADR from your QPPV stating that for a tablet product you make there is no efficacy, you also make the product in an injection and a liquid but have received no events of lack of efficacy from those products. What are you going to do?
You find out that the API has changed supplier for this batch. The new API has also been used for injections and liquid batches.
You find out that the process uses recycled solvents . What are your concerns?
You receive a call from the QPPV they inform you they are receiving increasing reports that there is a lack of efficacy on a tablet product. You prepare both a tablet and injection from the same API.
What is the QPPV, how would you expect to interact with them as a QP
What is pharmacoviligence
Discussed
why might see this in the tablet and not the OSD
Your procurement team want to change API supplier they have found a cheaper alternative – what would your concerns be over this.
a. Discussion around nitrosamines later on
What is the difference between Chemical and biological API? What is critical step in biological production? How would typical biological CoA look like? What are the production steps? How do they exactly differ?
What is critical step in biological production?
How would typical biological CoA look like?
How would typical biological CoA look like?
What are the production steps? How do they exactly differ?
You are certifying an oral solution and you see that appearance is not matching. The registered spec says to be white/whitish, but you see it is pale yellow/yellow. What would you do? There are several batches which are certified with yellow appearance.
The talk led to nitrosamine contamination and recall.
