How do you adjust an API quantity for potency (as-is, anhydrous or dried basis) in a batch formula?

1The formula for each basis.

A potency-adjusted master formula states the API at 100% content and scales it by each lot’s real content, because the batch must be formulated “with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient”.¹ Convert the certificate’s assay to the as-is basis, the material as it sits in the container, then divide:

Quantity to weigh (Q) = Q₀ × 100 ÷ A, where Q₀ is the master formula quantity at 100% content and A is the as-is assay. The potency factor is 100 ÷ A.

Pair each basis with its test: anhydrous with a water result, dried with loss on drying, which is not specific for water; ICH Q6A prefers “a detection procedure that is specific for water (e.g., Karl Fischer titration)”.² Karl Fischer water includes a hydrate’s water of crystallisation, so for an anhydrous label claim the water-corrected assay is already the as-is content; applying a hydrate-to-anhydrous molecular weight ratio as well removes the water twice. For a free-base claim and a salt assay, first multiply Q₀ by the salt’s molecular weight over the base’s. For potency in units, Q is the units required divided by the as-is units per milligram.

1.1For a reference or working standard.

The standard’s content enters every assay result, so it too must be on the basis of the standard as weighed. Use a primary standard as its supplier directs:³ one labelled to be dried before use is dried as the label says, and its stated value then applies as given. A Ph. Eur. CRS is used as received, and dried it “will no longer be suitable for its intended use”; its leaflet value already accounts for water and solvent.⁴⁵ Convert only a value stated on a different basis from the material as weighed. Assigning a working standard’s value is worked through in working standard qualification.

2Example: one lot, three readings of 98.7%.

Example, invented. Product A 100 mg tablets, Batch 26-041: 500,000 tablets of 250 mg. The label claim is 100 mg of anhydrous API A per tablet. The master formula holds 50.00 kg of API A at 100% content, 67.50 kg of microcrystalline cellulose as the compensating filler, 5.00 kg of croscarmellose sodium and 2.50 kg of magnesium stearate: 125.00 kg. QC released API A lot A-2611 with an assay of 98.7% on the anhydrous basis and 4.2% water by Karl Fischer.

The same figure gives three quantities, depending on the basis printed beside it:

Read the anhydrous result as if it were as-is and the operator weighs 50.66 kg, which holds 50.66 × 94.5546% = 47.90 kg of API A: 95.8% of the label claim, with every weighing in tolerance. Record the basis next to every assay value, not only in the specification.

Set the weighing tolerance around the adjusted 52.88 kg, the weight the second person checks as “correct as stated in the batch production records”.¹ A tolerance of ±0.10 kg accepts 52.78 to 52.98 kg, and its low limit delivers 99.8% of the claim; a tolerance above the target only keeps every accepted weight at 100% or more. The same ±0.10 kg around the nominal 50.00 kg would pass 50.10 kg: 94.7% of the claim. Whether the balance can weigh to that tolerance is a minimum weight question.

3Test cases for the spreadsheet or MES.

Input to and output from a computer system of formulas must be “checked for accuracy”, and Annex 11 asks validation test scenarios to consider “system (process) parameter limits, data limits and error handling”.⁶⁷ These cases come from the example, with a master record range of 90.0 to 102.0% as-is.

4What the master formula must say.

Part 211 does not mention potency adjustment by name. It permits “reasonable variations” in component quantities only if “they are justified in the master production and control records”, and wants “a statement concerning any calculated excess of component”.⁸ A factor that moves the API and filler from batch to batch is such a variation. For the dossier, EMA says that where the quantity of an active ingredient “is calculated from the actual assay value of the batch of that active ingredient”, “this should be stated and justified”, and an ingredient used to keep the batch mass constant “should also be indicated”.⁹ Because the factorisation sits in the registered batch formula (CTD 3.2.P.3.2), adding it to an authorised EU product changes that formula; EU variations covers the filing.¹⁰⁹

Copy these entries into the master record and fill the brackets.

5Who does what, and when.

1. Development and regulatory affairs choose the basis and the compensating excipient, and state the factorisation in the dossier’s batch formula.¹⁰⁹
2. One person prepares the master record, a second checks it independently, and the quality unit approves it.⁸¹³
3. QC approves the API lot and the assay and water values to use. A supplier’s certificate can replace your own assay in the US only with your own identity test and validated reliability of the supplier’s results; in the EU, only with an identity test on each batch, a justified reliance and a full analysis at intervals to check the certificate.¹⁴¹⁵
4. At dispensing, a second person or validated electronic means checks the inputs before the weight is calculated.⁶⁷ After weighing, a second person, or one person checking automated equipment, confirms the weight against the batch record.¹¹⁵
5. The batch record keeps the API lot and the quantities actually weighed; QA reviews it before release and investigates any unexplained discrepancy.¹⁶¹¹¹⁷

FDA’s drug inspection programme lists “Adequate procedure and practice for charge-in of components” and “Formulation/manufacturing at not less than 100 percent” among the production areas investigators cover.¹⁸ Be ready to trace any weighed quantity back to the certificate, and to show how the calculation was validated and who can change it.⁶

6Decisions at the balance.

7How FDA enforces it.

Your firm failed to revise your manufacturing formulation after replacing the (b)(4)% ethanol with a lower strength ethanol.

Aromas Para El Alma S.A., warning letter of 10 September 2024, citing 21 CFR 211.101. The firm switched a hand sanitiser and a spray to a lower-strength ethanol without changing the formula, and batches below the labelled ethanol content were released for distribution.²¹

You then adjusted the potency by adding additional APIs and re-mixing the batch. The batch was retested, and the potency assay was found within specification. However, the root cause of the low potency was not determined.

CTK OTC Laboratories LLC, formerly FMK Labs, warning letter of 19 May 2025, citing 21 CFR 211.192. A factor set in the master record before weighing is planned; topping up a batch that has already failed is not.²²

8EU GMP, PIC/S and the MHRA.

EU GMP sets the same duties in its own words: a manufacturing formula listing “all starting materials to be used, with the amount of each”, a batch record of “the quantities of each starting material actually weighed”, and an independent check of each weight, recorded.¹¹¹⁵ PIC/S, whose participating authorities include the MHRA, describes its GMP Guide and the EU’s as “practically identical”.²³²⁴ For what the batch record must hold, see what goes in a batch production record; for the certificate behind the factor, see what a certificate of analysis must contain.

9How it runs in Seal.

In Seal’s weigh and dispense workflow, potency or moisture corrections are kept with their source values and reviewed calculation, and the protocol defines rounding, tolerances and verification. The container scan, the gross, tare and net readings and the verification are recorded against the batch step, and the version used for the actual dispense is preserved rather than recalculated against a revised formulation.

In electronic batch records, calculations such as potency adjustment are versioned process logic: a changed formula is a controlled revision tested against representative cases before it takes effect, and each calculated value keeps its formula version, inputs, rounding and result. Neil can draft dispensing checks from your dispensing instructions; the manufacturing owner verifies the devices, units and exception behaviour and releases the workflow under change control.