Why “API” is more than a chemistry label

In day‑to‑day operations, “API” is often used as shorthand for “the active.” But in quality and supply contexts, the classification drives real downstream outcomes:

• which GMP framework is expected,

• what your specification must control (especially impurities),

• what supplier documentation you can rely on (and when you must verify),

• and what storage/shipping controls you must define to avoid avoidable excursions.

ICH Q7 defines an Active Pharmaceutical Ingredient (API) (drug substance) as any substance or mixture intended to be used in manufacturing a drug product that becomes the active ingredient and is intended to furnish pharmacological activity or other direct effect.
ICH Q7 also notes that legal classification as an API can vary by region, and when a material is classified as an API in the region where it is manufactured or used, it should be manufactured according to ICH Q7.

1) Confirm whether your material is an API, intermediate, or excipient before writing the spec

This is the fastest way to prevent two expensive mistakes:

• writing an “API‑like” spec for something that is actually an intermediate (over‑controls, delays), or

• treating an API like a research material and discovering late that your spec, documentation, and handling controls are not phase‑appropriate.

Practical definitions you can apply

API (drug substance)

Use the ICH Q7 definition as your baseline in global discussions.

Intermediate

ICH Q7 defines an intermediate as a material produced during steps of API processing that undergoes further molecular change or purification before it becomes an API; intermediates may or may not be isolated.

Excipient (inactive ingredient)

In EU labeling guidance, excipients are defined as constituents of a medicinal product other than the active substance and the packaging material. (Public Health)
In U.S. CGMP definitions (21 CFR 210.3), an inactive ingredient is any component other than an active ingredient, and an active ingredient is any component intended to furnish pharmacological activity or other direct effect. (Legal Information Institute)

A simple classification decision tree (copy/paste)

1. Is the material intended to become the active ingredient in a drug product (now or later in your program)?

   • Yes → treat as API/drug substance (phase‑appropriate controls; ICH Q7 logic applies).

2. Is the material produced during processing of an API and expected to undergo additional molecular change or purification before it becomes the API?

   • Yes → it is an intermediate (still controlled, but your spec and documentation should match its role).

3. Is it part of the finished formulation but not the active substance (and not packaging)?

   • Yes → excipient/inactive ingredient. (Public Health)

What changes once you classify correctly

Once the material is classified, your specification should be scientifically sound and consistent with how the material is made and used. ICH Q7 states that specifications, sampling plans, and test procedures should be scientifically sound and appropriate; and that appropriate specifications should be established for APIs consistent with the manufacturing process (including impurity controls).

Copy/paste: “Material Classification Memo” (minimum viable)

Material name / code:
Intended use (research / nonclinical / clinical / commercial):
Classification: API / Intermediate / Excipient
Rationale (one paragraph): (tie to intended use and definitions)
Spec owner:
Quality reviewer:
Supplier(s)/site(s):
Implications: (e.g., GMP expectations, CoA requirements, shipping conditions)

2) Request a sample CoA and specification when evaluating a new supplier

Teams often wait until the first shipment to discover that:

• the supplier’s CoA doesn’t include numeric results,

• the original manufacturer identity is unclear (brokered supply),

• or the supplier spec doesn’t align with your intended use (e.g., missing known critical impurities or residual solvent limits).

What a “good” CoA should include (baseline expectations)

ICH Q7 provides very concrete expectations for Certificates of Analysis (CoAs), including:

• CoA issued (authentic) for each batch on request,

• name/grade, batch number, release date,

• expiry date or retest date where applicable,

• each test performed, acceptance limits, and numerical results (when numeric),

• dated and signed by authorized quality unit personnel,

• identification of original manufacturer (and how repackers/reprocessors should reference them).

Copy/paste: CoA review checklist (quick screen)

• Does the CoA list tests + acceptance criteria + results (not just “Pass”)?

• Is it signed/authorized by Quality and dated?

• Is the original manufacturer clearly identified (especially if a broker/repacker is involved)?

• Are expiry/retest expectations clear and consistent on label/CoA?

• Does it match your draft/spec (tests and limits) for the intended stage?

What to look for in the supplier specification

Your goal is not to copy/paste their spec. Your goal is to confirm it supports your intended use.

Minimum items to compare:

• identity test(s) and method references

• assay (and basis: as‑is / anhydrous / corrected)

• specified impurities (known/unknown, total)

• residual solvents (as applicable)

• water content / LOD (as applicable)

• physical form controls if relevant (polymorph, particle size)

• microbial limits if applicable for the material/use case

• packaging and storage conditions (and retest/expiry model)

ICH Q7 emphasizes that specifications and test procedures should be scientifically sound and appropriate, and API specifications should include impurity control and be consistent with the manufacturing process.

A key operational point: when can you rely on supplier testing?

If you plan to reduce incoming testing based on the supplier’s CoA, you need a defined reliability approach.

• ICH Q7 allows use of a supplier’s CoA in place of other tests (after identity testing), provided the manufacturer has a system to evaluate suppliers; it also recommends full analysis on at least three batches before reducing in‑house testing and checking CoA reliability at regular intervals.

• U.S. CGMP (21 CFR 211.84) similarly allows acceptance of a supplier’s report of analysis in lieu of full testing (after at least one specific identity test) if the manufacturer establishes reliability through validation at appropriate intervals. (Legal Information Institute)

Copy/paste: “Supplier Spec + CoA Evaluation Summary” (one page)

Supplier / site:
Material / grade:
Intended use stage:
Sample CoA reviewed (batch # / date):
Spec reviewed (version/date):

Fit gaps (must fix before PO):

• Gap 1:

• Gap 2:

Acceptable gaps (won’t increase real risk for this stage):

• Item 1:

CoA reliability plan (if relying on supplier results):

• Initial full testing plan: (e.g., first 3 lots)

• Ongoing verification frequency: (e.g., every Nth lot or annually)

• Owner:

3) Define storage and shipping needs early to avoid avoidable excursions

Most “shipping problems” are actually “requirements definition problems.” If storage/shipping expectations are unclear at RFQ/PO stage, the first shipment becomes an uncontrolled experiment.

What to define early (minimum viable)

A) Storage condition and allowable controls

ICH Q7 expects facilities for storage under appropriate conditions (controlled temperature/humidity when necessary) and records of those conditions when critical to material characteristics.

B) Labeling requirements

ICH Q7 states labels should indicate storage conditions when critical to assure quality, and when transferring outside the manufacturer’s control, special transport conditions and other required information should be included on the label.

C) Transport expectations and contractor responsibility

ICH Q7 states APIs and intermediates should be transported in a manner that does not adversely affect quality; special transport/storage conditions should be stated on the label; and the manufacturer should ensure the transportation contractor knows and follows appropriate transport and storage conditions.

D) Tamper evidence

ICH Q7 notes that containers transported outside the manufacturer’s control should be sealed so that breach or absence alerts the recipient to the possibility contents may have been altered.

Copy/paste: Storage & Shipping Requirements Sheet (one page)

Material:
Classification: API / Intermediate / Excipient
Storage condition: (e.g., 2–8°C / CRT / protect from light / dry)
Packaging requirement: (liner material, desiccant, nitrogen purge, etc.)
Label statements required: (storage + any special transport conditions)
Shipping mode constraints: (air/ground; max transit time)
Temperature monitoring required: Y/N (and who reviews data)
Seal/tamper evidence required: (type)
Excursion handling: (who owns disposition; what evidence needed)
Receiving checks: (visual inspection, label match, seal intact, CoA present)

4) Record decisions, owners, and due dates

This is the difference between a repeatable procurement/quality process and a “hero‑based” process.

Copy/paste: API 101 decision log

5) File supporting documents with the final record

Your “final record” should allow someone to reconstruct: what the material is, why you classified it that way, what you required, and why you accepted a supplier/lane.

Copy/paste: Filing checklist (practical)

• Material classification memo (Step 1)

• Approved spec (current stage) and change history

• Sample CoA(s) reviewed + CoA review checklist

• Supplier spec reviewed + gap assessment

• CoA reliability plan (if applicable)

• Storage & shipping requirements sheet (Step 3)

• First‑lot receiving record (inspection, label match, seal status, disposition)

• Any deviations/excursion assessments and outcomes

6) Schedule a follow‑up review to capture lessons learned

A short review after first receipt (or first 2–3 lots) prevents “slow drift” where informal decisions become permanent without being tested.

Suggested cadence

• After first lot (or first shipment for a new lane): confirm spec alignment, documentation completeness, and any shipping vulnerabilities.

• After first 3 lots: confirm variability trends and whether CoA reliance assumptions are valid.

Copy/paste: 30‑minute lessons‑learned agenda

1. Did the supplier documentation match what we expected (CoA content, signatures, manufacturer identity)?

2. Did we see any gaps in the spec (missing impurities, missing physical form controls, unclear assay basis)?

3. Did shipping/storage perform as intended (labels, seals, conditions, handoffs)?

4. Any actions to update the spec, supplier requirements, or shipping sheet? (owner + due date)

Practical closing

If you implement only three actions from this checklist:

1. Classify the material correctly before writing the spec (API vs intermediate vs excipient),

2. Review a sample CoA + spec before the first PO (and define whether you will rely on supplier testing),

3. Define storage and shipping requirements early (label statements, special transport conditions, sealing),

…you will prevent a large share of avoidable receiving holds, excursion investigations, and “late discovery” quality gaps.

Checklist

• Confirm whether your material is an API, intermediate, or excipient before writing the spec.
• Request a sample CoA and specification when evaluating a new supplier.
• Define storage and shipping needs early to avoid avoidable excursions.
• Record decisions, owners, and due dates.
• File supporting documents with the final record.
• Schedule a follow‑up review to capture lessons learned.

Notes:

This checklist is for educational use only and does not replace your internal procedures.