Pharmaceutical-grade active pharmaceutical ingredient (API)

01

Qualify the manufacturer, the documents and the supply chain

ICH Q7 is the GMP guide for APIs. It applies from the point where an API starting material, a material incorporated as a significant structural fragment of the API, enters the process. It requires a quality unit independent of production that covers both quality assurance and quality control, a formal change control system for changes in raw materials, specifications, methods, facilities, equipment and processing steps, and records kept for at least 1 year after the batch expiry date, or 3 years after complete distribution for APIs with retest dates. [1]

Q7 calls for an authentic batch certificate on request, identifying the substance, grade where appropriate, batch and release date. It distinguishes expiry dates on the label and certificate from retest dates on the label and/or certificate; numerical results apply where the test is numerical. Authorised quality personnel date and sign the certificate. Stability studies support expiry or retest dating. Reserve samples for expiry-dated batches are retained for one year after expiry or three years after distribution, whichever is longer; for retest-dated APIs, Q7 separately states three years after complete distribution by the manufacturer. [1]

Agents, brokers, traders, distributors, repackers and relabellers are expected to comply with GMP, keep full traceability including the identity and address of the original manufacturer, its batch number and all authentic certificates of analysis, pass quality and regulatory information in both directions, and give the customer the name of the original manufacturer and the batch numbers supplied. Contract manufacturers and laboratories also fall under Q7 and should be evaluated by the contract giver under a written agreement. [1]

Ask for the original manufacturer's name and site address, its GMP inspection or certification history, the regulatory filing to be referenced for your market, the specification and a sample certificate of analysis, the retest or expiry period with stability data, change-notification terms and, for traders, the full traceability documents.

02

Set impurity and residual-solvent limits for your dose

ICH Q3A(R2) covers impurities in new drug substances made by chemical synthesis. For a maximum daily dose of up to 2 g it sets a reporting threshold of 0.05%, an identification threshold of 0.10% or 1.0 mg per day intake, whichever is lower, and a qualification threshold of 0.15% or 1.0 mg per day, whichever is lower; above 2 g per day the thresholds are 0.03%, 0.05% and 0.05%. Higher reporting thresholds need scientific justification, and lower thresholds can be appropriate for unusually toxic impurities. Impurities above the identification threshold should be identified, and those above the qualification threshold qualified by safety data. [2]

The archived Q3C(R8) source places residual solvents in three classes: Class 1 solvents to be avoided (benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1,500 ppm); Class 2 solvents to be limited, with Option 1 concentration limits calculated as 1,000 × PDE / dose assuming 10 g of product daily; and Class 3 solvents of low toxic potential, where 50 mg per day or less, corresponding to 5,000 ppm or 0.5% under Option 1, is acceptable without justification. The later Q3C(R9) analytical-procedure section allows a non-specific method such as loss on drying for Class 3 solvents only when properly validated, including the effect of solvent volatility on the method. Class membership alone does not establish that the proposed test controls the solvents present. [5] [3]

Editorial calculation: assume a maximum daily drug-substance dose of 0.5 g, equivalent to 500 mg, within the Q3A(R2) new chemically synthesised drug-substance scope. Then (1.0 mg/day ÷ 500 mg/day) × 100% = 0.20%. For this assumed dose, 0.10% identification and 0.15% qualification are lower than the daily-intake alternative. This reproduces the basis of the guideline’s 0.5 g example; it is not a universal API specification, and unusually toxic impurities can need lower thresholds. [2]

Nitrosamine assessment is separate from ordinary Q3A thresholds. FDA’s CDER page distinguishes small-molecule nitrosamines from API-related NDSRIs and provides recommended lifetime acceptable intakes, including NDMA 96 ng/day and NDEA 26.5 ng/day in its compound-specific table. Use the applicable impurity entry and exposure conditions; the page describes these recommendations as nonbinding and subject to updates. [4]

Editorial unit conversion: assuming a maximum daily API dose of exactly 1 g and all 96 ng/day of NDMA is allocated to that API, 96 ng/g = 0.096 µg/g = 0.096 ppm by mass (0.0000096%). This assumed allocation does not account for formation or other contributions in the finished medicine. Assess the actual sources, maximum daily dose, relevant acceptable intake and analytical sensitivity. [4]

Give the supplier the maximum daily dose and route, the pharmacopoeial monograph or in-house specification, the solvents used in the last steps as you understand them, and any polymorph, particle size or water content needed by your formulation.

03

Original manufacturers, contract sites and API traders

04

Specification, batch certificate and stability records

05

Substance-specific tests and dose-dependent impurity conditions

06

Send the substance, dose and documentation needs together

Paste it into your enquiry below or into an email to a maker, then replace every bracket.

Substance: [name; grade; monograph or specification]
Dose: [maximum daily dose; route]
Quantity: [batch size; annual volume]
Manufacturer: [original site; GMP status; filing reference]
Documents: [CoA; stability; change notification; traceability]
Physical: [polymorph; particle size; water]
Packaging: [container; storage; retest period]

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