How many batches must go into the ongoing stability programme each year?

1How many batches each year: the rules side by side.

Primary stability studies set the shelf life, commitment studies confirm it on production batches, and ongoing studies then check, year by year, that commercial batches still meet it.¹ EU GMP sets the clearest annual number: “Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none are produced during that year).”²

FDA’s warning letters ask for “an ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid”.¹³¹⁴

“Every strength and every primary packaging type” can be read two ways. The combination reading places each strength in each pack type, four placements in the example below. The coverage reading needs each strength and each pack type to appear once, three placements. The combination reading is the conservative one; the draft ICH Q1 wording, “each strength of the drug product covering the container closure systems”, leans towards coverage.²¹ “Primary packaging type” reads most naturally as the kind of container closure system, such as a bottle or a blister, rather than each pack count.²¹¹ Write your reading, and the reason for it, into the protocol.

2Commitment batches and ongoing batches.

When the submission’s long-term data do not cover the shelf life on three production batches, the applicant commits to continue or start studies on production batches, to a total of at least three, through the proposed shelf life. FDA’s ANDA Q&A points to this ICH Q1A(R2) commitment, then adds the annual placement.¹⁵⁹ For APIs, ICH Q7 puts the order plainly: “Normally the first three commercial production batches” go on study to confirm the date, fewer where data show at least two years’ stability, and “Thereafter” at least one batch a year.¹⁰

The draft ICH Q1 separates the two: a commitment study follows the primary protocol unless justified, while ongoing studies “are not required to align with the primary stability protocol”.¹ EU GMP 6.32 and the draft do not say whether a commitment batch made in a given year also fills that year’s ongoing placement. If your protocol counts it, say so, and check that its testing meets the ongoing protocol too.

3Ongoing stability protocol checklist.

Copy these lines into the protocol. Each is tied to the clause that asks for it.

For Canada, add traceability to the master formulae, packaging size, storage tolerances and sample orientation. For preserved products, Health Canada also asks for preservative content or antimicrobial effectiveness at least at the initial time point and at expiry; for sterile products, sterility at the same two points, or container closure integrity at the end of shelf life instead.⁵

4How often to test, and for how long.

• Duration. The protocol runs to the end of the shelf life, or the retest period for an API.²¹¹¹
• Finished products. WHO says 6-month and annual time points are generally sufficient for ongoing studies.¹¹ For products with an established shelf life and a consistent stability history, Health Canada asks for testing at least every year, with at least five time points including the initial and final ones, unless the marketing authorisation says otherwise.⁵
• APIs. At least annually under ICH Q7; WHO generally expects at least every 6 months in the first year, then annually.¹⁰¹¹ For APIs with shelf lives of a year or less, Q7 gives monthly for three months, then every three months.¹⁰
• Biologicals. EU GMP 6.32 makes no exception for them. ICH Q5C bases dating on real-time data, and where a filing relied on pilot-scale batches it asks for a commitment to place the first 3 manufacturing-scale batches on long-term study after approval.¹⁸²
• Later in the product’s life. ICH Q7 and Q5C already allow dropping a time point, such as 9 months, once data show stability is not compromised. The draft ICH Q1 adds attributes not related to stability.¹⁰¹⁸¹

5Example: a year’s placements for a product family.

This example is invented. A tablet family comes in 5, 10 and 20 mg, compressed at different weights from one granulation. All three strengths are packed in HDPE bottles of 30 and 90 tablets; the 10 mg also goes into an Alu/Alu blister. Shelf life is 36 months. In 2027 the site makes 4 batches of 5 mg, 9 of 10 mg and 5 of 20 mg. Each placement is pulled at 6, 12, 24 and 36 months, after the release result.

The judgement calls behind the table:

1. Which bottle. Read as pack type, 6.32 needs only one bottle size. The protocol picks the 30-count bottle because it has the higher water vapour permeation per tablet, one of the characteristics ICH Q1D lists for choosing extremes.¹⁶
2. Why bracketing holds. ICH Q1D gives tablets compressed at different weights from the same granulation as a case where bracketing applies. The 10 mg blister cannot be bracketed: no other strength uses that pack.¹⁶
3. Which 10 mg batch. QA picks the batch whose bulk was held longest before packing, since EU GMP asks for long bulk holds to be considered.²
4. The matrix, and its cost. Every placement is tested at 6, 12 and 36 months; the 24-month pull rotates, this year to the 20 mg bottle. That matrixes across a bottle and a blister, two container closure systems, which ICH Q1D allows with justification, generally supporting data such as relative moisture vapour transmission rates. Combining bracketing with matrixing needs “careful consideration and scientific justification”.¹⁶ Two placements also go from 12 to 36 months untested. Weigh that against 6.32’s “sufficient amount of data to allow for trend analysis”.² In the US it runs against ITG 41, which calls annual testing “minimal for compliance with CGMPs”, and in Canada, which asks for testing at least every year, the marketing authorisation would have to allow it.⁸⁵
5. The second half of the year. A change to the blister forming film approved in August is a significant change to the package, so one 10 mg batch packed after it joins the programme as an extra blister placement.²

Under the draft ICH Q1, a reduced design should be justified in the regulatory submission where applicable, and one used at approval is followed until the configuration changes.¹ In the US, the stability protocol in an NDA or ANDA is part of the approval: changing it, for example from a full design to this one, is a prior approval supplement, while adding time points, or deleting those beyond the approved expiry date, goes in the annual report.¹⁹ A licensed biologic reports changes under 21 CFR 601.12 by their potential for adverse effect.²⁰

6Decision aid: the years that are not typical.

7What the results feed.

Results go to key personnel, “in particular, to the Qualified Person(s)”.² Out-of-specification results and significant atypical trends are investigated; in the EU, a confirmed failure or significant negative trend affecting batches on the market is reported to the competent authorities, and the possible impact on marketed batches is considered in consultation with them.² For an NDA or ANDA in the US, a distributed batch that fails its specification triggers a field alert report within 3 working days, and the annual report carries a status report on all product stability studies.¹⁷²¹ For a licensed biologic, a failure on a distributed lot that may affect safety, purity or potency can be a biological product deviation, reported on Form FDA 3486 within 45 calendar days.²² See OOS, OOT and OOE.

A written summary, with interim conclusions, is kept and reviewed periodically.² The EU product quality review includes “A review of the results of the stability monitoring programme and any adverse trends.”²³ See the annual product review.

8What inspectors cite.

FDA’s compliance policy guide on expiration dating lists “Lack of an ongoing testing program to verify product stability after the shelf life has been determined appropriate” among the situations for which it recommends regulatory action, such as a warning letter.²⁴

“Your firm failed to place at least one batch of each API manufactured in 2021, 2022, and 2023 on stability.” Micro Orgo Chem, FDA warning letter 320-25-21, 3 December 2024¹³

Placing batches is not enough. FDA wrote to one OTC manufacturer:

“Your firm missed stability time points, missed stability tests, or performed incorrect tests on batches placed into your stability program.” K.C. Pharmaceuticals, FDA warning letter 320-26-112, 12 August 2026²⁵

MHRA’s published examples from its 2016 inspections show the failure after the results arrive:

“There had been numerous stability failures (including pre-shelf life expiry) identified but these had not been formally assessed by the QPs or the impact on continued certification considered.” MHRA GMP Inspection Deficiency Data Trend 2016²⁶

The same list includes a contract manufacturer that did not tell the marketing authorisation holders about stability failures.²⁶

9How it runs in Seal.

In Seal, stability keeps the protocol, each physical pull and each result as connected records, so a missing time point becomes owned work when it appears rather than a discovery at report time. A protocol amendment is a new version: executed pulls keep the version they followed, and ongoing placements carry forward with their owners and due dates.

Neil can plan the next stability pulls from protocol windows, chamber inventory and laboratory capacity, and review a stability trend before study review; the study planner and study owner decide. The annual product quality review evaluates stability alongside batch outcomes, complaints, changes and supplier history for the same product, sites and period.