Product release after transport: from manual review to release by exception

Three releases that are easy to confuse

Annex 16 names the link between them. Batch release, it says, ends with the transfer to saleable stock, which has to take the QP's certification into account, and where that transfer happens at another site, the arrangement is set down in a written agreement between the sites. The EU GDP guidelines say the same from the receiving end: batches go into saleable stock only once the site has assurance, under written procedures, that they are authorized for sale.

The two can overlap: where a batch travels before it is certified, as when finished product made outside the EU is shipped to the importing site, Annex 16 asks the QP to take the conditions of storage and transport into account before certifying it, so the transport record becomes part of the certification.

The rest of the EU guidelines are covered in our guide to good distribution practice.

What the quality team checks on receipt

The guidance sets the checks in general terms. EU GDP asks the receiving function to confirm that the consignment is correct, comes from an approved supplier, and has not been visibly damaged, and to move products that need special storage into it first. WHO adds that the transport temperature data, where appropriate, is reviewed on receipt, to make sure the required conditions were maintained, and that nothing goes into saleable stock until an authorized release is obtained. In practice, the review covers five things:

The record against the range

Every reading compared with the range on the label or agreed with the manufacturer. EU GDP asks that storage conditions be kept, in transit, within the limits the manufacturer describes or the outer packaging states.

The excursions

each period outside the range, with how long it lasted and how far it went. Under EU GDP, an excursion in transit is reported to the distributor and the recipient and investigated under a written procedure, whatever the release decision.

The stability budget

for a product that has one, how much of its allowed time outside the storage condition this shipment used, and how much is left for the rest of the chain.

Completeness

whether the record covers the whole journey without gaps and belongs to this shipment. A gap in the record is a period nobody can account for.

The chain of custody

whether the shipment came from the expected sender and arrived where it was meant to, with seals intact and no signs of tampering. WHO lists seal intactness and signs of tampering among the checks at receipt, and EU GDP requires delivery to the address on the delivery note.

Why manual review is slow

When the record comes from a device read on arrival, the review cannot start until someone has found the device in the shipment, stopped it, read it out, and filed the result, often as a PDF report. A reviewer then opens the file, checks the readings against the product's limits, and signs the release or raises a deviation.

The product waits in quarantine the whole time, held apart from saleable stock until someone decides.

The cost sits in the clean records. Where most shipments arrive within their range, a manual process still reviews every one with the same care, so the queue is set by volume rather than by risk.

Defining release by exception

Release by exception turns that around. The quality team agrees in advance, in writing, what a releasable record looks like for each product. A validated system checks each arriving record against those criteria. Records that meet them are released without a person reviewing them; records that do not, or that cannot be evaluated, go to a person, who decides as before.

None of the GDP or GMP texts cited here uses the phrase, and none of them requires automated release. What they do set are the conditions a system that makes routine quality decisions has to meet.

Automating release from the temperature record, step by step

1. 1

   Set the criteria

   For each product: its temperature range, its stability budget and how much of it a shipment may use, any limit on freeze and thaw cycles, and what counts as a complete record. The criteria come from the manufacturer's stability data and are approved in the quality system like any other procedure.

2. 2

   Capture the record

   Each shipment carries a device whose readings are tied to that shipment and kept in a validated system with an audit trail.

3. 3

   Evaluate on arrival

   When the shipment is received, the system checks each product's record against that product's criteria: range, excursions, budget, and completeness.

4. 4

   Release or route

   A record that meets every criterion is released, and the release is recorded with the criteria it was judged against. A record that fails any of them, or is incomplete, stays in quarantine and goes to a person.

5. 5

   Review the exceptions and the system

   A person decides the exceptions as before. The system itself is evaluated periodically, as EU GMP Annex 11 asks of computerized systems, to confirm it remains in a valid state.

What has to be in place

Automating the decision does not lower the bar it has to meet. Annex 11, the EU GMP guidance on computerized systems, puts it in one sentence: where a computerized system replaces a manual operation, there should be no resultant decrease in product quality, process control, or quality assurance.

A validated system

EU GDP: before a computerized system is brought into use, it is shown through validation or verification that it achieves the desired results accurately, consistently, and reproducibly. In the US, 21 CFR Part 11 asks for systems holding electronic records to be validated for accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.

Electronic quarantine that holds

EU GDP and WHO both allow product awaiting a decision to be held apart electronically rather than physically, provided the system gives equivalent security and is validated.

A record whose integrity holds

The US Food and Drug Administration (FDA) defines data integrity as the completeness, consistency, and accuracy of data, and expects such data to be attributable, legible, contemporaneously recorded, original or a true copy, and accurate, known as ALCOA. Annex 11 asks systems that exchange data electronically to have built-in checks for its correct and secure entry and processing. Automatic criteria are only as good as the record they read.

Approved criteria and stability data

the criteria rest on the product's stability data, which comes from the manufacturer or marketing authorization holder, and they are approved before use. A product without stability data covering the conditions in question has nothing to automate, and stays with a person.

An audit trail

21 CFR 11.10(e) asks for secure, computer-generated, time-stamped audit trails of the actions that create, modify, or delete electronic records. Annex 11 asks for such an audit trail to be considered on the basis of risk, for the reason behind any change or deletion of GMP-relevant data to be documented, and for audit trails to be regularly reviewed. With one in place, every automatic release, and every change to a criterion, can be traced.

Written agreements

EU GDP requires a written contract that clearly sets out each party's duties for any outsourced activity, and Annex 11 requires formal agreements with third parties that provide or support a computerized system. Where the record comes from a monitoring provider, the quality agreement says who supplies the data, who sets the criteria, and who decides the exceptions.

Named accountability

the decision stays with the people the rules name. Under EU GDP the Responsible Person may delegate duties but not responsibilities, and under 21 CFR 211.22 the quality control unit has the responsibility and authority to approve or reject drug products. Release by exception hands over the routine work, not the responsibility for it.

What 21 CFR Part 11, Annex 11, and ALCOA+ ask of the record and of the system that holds it is set out in our guide to data integrity for temperature records.

Excursions within a stability budget

An excursion is not the same as damage. Whether the product can still be used is judged against its stability data, and many products have data that allows some time outside the storage condition without significant risk to quality. That allowance, the stability budget, is cumulative: every excursion in the product's life spends part of it.

This is what makes release by exception more than a check that the record stayed in range. If the criteria include the budget, a shipment with an excursion the budget absorbs can be released automatically, because the decision a person would have made from the same stability data is already written into the criteria. A shipment that goes beyond the budget, or a product with no agreed budget, goes to a person.

Two things do not change. Under EU GDP, the excursion is still reported to the distributor and the recipient, and handled under the procedure for investigating excursions, even when the product is released. And the part of the budget the shipment used is spent: the next site can judge only against what is left, which is why a product with a small budget needs its exposure tracked at each step of the chain.

How excursions are defined, reported, and assessed is in our guide to temperature excursions, and where a single summary figure can and cannot be used in that assessment is in our guide to mean kinetic temperature.

Where the record comes from

Release by exception needs the record in the system when the shipment arrives. A device read on arrival can feed it once someone has read it out. A device that reports during the trip has the record complete as the shipment lands, so the evaluation can run at receipt. How the device types differ is in our guide to cold chain monitoring devices, and the case for reporting in transit, with the cases where it does not pay, in Why real-time temperature monitoring, and when it isn't worth it.

Where Controlant fits

Controlant's Zero-Touch Release releases pharmaceutical products for further processing or distribution when every product in the shipment stayed within its stability budget, including a product that had an excursion the budget absorbed. Each product is checked on arrival against its own digitized stability profile, and only a product beyond its budget goes to the customer's quality team. The Controlant Platform is validated to comply with FDA 21 CFR Part 11 and EU GMP Annex 11. At Roche, the approach has automated up to 99.5% of product releases with no human intervention, according to a joint Roche and Controlant presentation at LogiPharma EU 2023.