Hold Time Study (HTS) – Proving the Fitness-for-Use of In-Process Materials Between Steps

This topic is part of the SG Systems Global regulatory & operations glossary.

Updated October 2025 • Process Validation & Micro/Chemical Stability • GxP • MES, QMS, WMS

Hold Time Study (HTS) is the structured demonstration that an in-process material, bulk, intermediate, or component remains suitable for its intended use when held between manufacturing steps under defined conditions of time, temperature, and container/closure. HTS spans sterile and non-sterile pharmaceuticals, biologics, medical devices with wet chemistries, food and dietary supplements, and even labeling/packaging intermediates (e.g., printed lots staged before application). The objective is simple but unforgiving: define the maximum allowable hold time (MAHT) and conditions such that critical quality attributes (CQAs) and microbiological or physical parameters do not drift out of specification, that mix homogeneity or potency does not stratify or degrade, and that the next step can proceed without increased risk. An HTS is not a guess; it is a protocolized, sampled, and statistically defensible study linked to the process design space and to routine controls enforced in the eBMR.

“Hold time is part of the process—not a scheduling buffer. If you cannot prove it, you cannot use it.”

1) What a Hold Time Study Covers

HTS addresses the time window between the end of one controlled step and the start of the next: post-granulation pre-drying, post-solution make-up pre-filtration, post-sterile filtration pre-fill, bulk liquid storage before final packaging, coated product staging before blistering, cleaned component storage before use, and staged labels/components awaiting application. The study defines start of clock (end of prior step), conditions (container/closure, headspace, mixing/rest state, agitation speed, light protection, environmental monitoring class), interruptions (temporary line stops), and stop criteria (start of next step, re-mix requirement, re-test before use). Acceptance criteria span chemistry (assay, degradants, pH, osmolality), microbiology/bioburden/endotoxin where applicable, physicals (viscosity, particle size, hardness/friability), and identification/label integrity where staging touches packaging. The output is a maximum allowable hold time with clear use instructions, sampling points, and actions on exceedance.

2) Designing a Defensible HTS: Worst-Case by Design

Good practice starts with risk assessment: map CQAs and process parameters, identify degradation mechanisms (hydrolysis, oxidation, microbial proliferation, adsorption to surfaces, stratification), and rank steps by sensitivity. Choose worst-case conditions deliberately: longest practical time, upper/lower temperature bounds from the process, minimal agitation if the routine process allows rest, maximum headspace/oxygen, and the most interactive container material. Define sampling at T0, mid-points, and beyond the proposed limit to show a stability trend, not just pass/fail at the edge. Use gravimetric precision and calibrated instruments (Asset Calibration Status) for quantitative attributes. Where multiple product strengths or container sizes exist, apply bracketing or matrixing with justification under CSV/statistics guidance, ensuring your coverage makes sense for viscosity, heat transfer, and surface-to-volume effects.

3) Executing the Study & Protecting Data Integrity

Protocol and report are controlled under Document Control with approval via Approval Workflow. Sampling is time-stamped, attributable, and traceable to the specific batch/equipment genealogy (Batch Genealogy). For electronic capture, comply with 21 CFR Part 11 and ALCOA+: unique users, contemporaneous entries, reason-for-change, immutable audit trails (Audit Trail). For microbiology, control pre-analytical variables (hold of the sample before test, transport conditions). Where environmental state matters, link to EM trends for the staging area. All equipment used in the study should be in qualified state (IQ/OQ/PQ).

4) From Results to Routine Control: Clocks, Labels, and Interlocks

Once the MAHT is established, embed it in the eMMR and enforce it at runtime through the eBMR: the system starts the timer upon step completion, displays elapsed and remaining time on the HMI, and blocks advancement if the next step is not initiated before expiry. For staged bulks and components, print hold labels with start time, expiry time, lot, and storage conditions using approved templates bound to GS1 / GTIN and internal master data, and require scan-back at use. In warehouses, pair MAHT with FEFO for short-dated intermediates and with Bin / Location rules to avoid “parking” sensitive bulks in uncontrolled areas. Any exceedance triggers automatic Deviation / NC, holds subsequent steps, and requires risk assessment prior to Batch Release or Finished Goods Release.

5) Chemical, Microbial, and Physical Dimensions

For chemistry-driven processes, watch pH drift, solvent loss, and degradants; consider oxygen permeation and adsorption to stainless or polymer surfaces. For biologics, include potency/activity and aggregation; headspace, shear, and temperature excursions can be decisive. For microbiological risk, differentiate bioburden growth vs endotoxin release and prove the container/closure and environment minimize ingress; link to Cleaning Validation where cleaned parts are held before assembly. For physical attributes, prove re-suspendability (no irreversible settling), viscosity stability (no thixotropic surprises), and homogeneity after defined re-mix time with acceptance limits aligned to the next unit operation’s capability. Where labels or printed cartons are held, control Barcode Validation, aging/ink set-off, and reconciliation to prevent mislabeling.

6) Lifecycle Management: Re-validation Triggers and APR/PQR

HTS is living evidence. Revisit when formulations, equipment surfaces, container/closures, mixing regimes, environmental classes, or maximum batch sizes change. Establish statistical trending in CPV: track near-expiry uses, out-of-trend attributes vs time, and override patterns. Summarize in APR/PQR with conclusions and CAPA where erosion of margin is detected. Train operators; ensure Change Control captures the downstream impact of hold-time shifts on labels, WMS rules, and schedule logic; and archive protocols/reports per Data Retention & Archival.

7) Common Failure Modes & How to Avoid Them

• Assuming time = stability. Extrapolating from “we’ve always done it.” Fix: protocolized study with worst-case conditions and trend data.
• Ignoring container/closure effects. Switching drums or liners changes oxygen and adsorption. Fix: include material of construction as a factor.
• Micro risk under-scoped. Bioburden may bloom at room temp. Fix: bracketing temperatures, EM linkage, and rapid methods where appropriate.
• Timer not enforced. Paper clocks slip. Fix: eBMR timers with HMI blocks and scan-back at point of use.
• Stratification unproven. “Re-mix for 5 min” without evidence. Fix: prove homogeneity after defined re-mix; specify speed/time.
• Study divorced from scheduling. MAHT shorter than real lead times. Fix: integrate planning constraints; adjust batch segmentation or resources.

8) Metrics That Prove Control

• On-time usage rate of intermediates before MAHT expiry.
• Blocked attempts (timer/temperature exceedance) per 1,000 steps and associated post-override defects.
• Re-mix verification success (homogeneity within limits) and time to readiness.
• Micro/chemistry drift vs time slope from CPV and frequency of near-limit results.
• Deviation recurrence related to hold-time; CAPA effectiveness trend.
• Inspection retrieval time for protocol/report + eBMR timers + print/scan logs.

9) How This Fits with V5

V5 by SG Systems Global operationalizes HTS across MES, QMS, and WMS. In V5 MES, step completion automatically starts the hold timer; HMIs display remaining time and temperature set-points; device links capture actual conditions; and interlocks block the next step on expiry. V5 WMS generates controlled hold labels with lot/expiry/conditions, enforces FEFO for short-dated intermediates, and prevents staging in non-compliant locations. In V5 QMS, HTS protocols/reports live under Document Control with Approval Workflow; deviations auto-open if timers/conditions are breached; and CAPAs drive systemic fixes. All records meet Part 11/audit trail expectations. Analytics trend blocked attempts, near-expiry usage, and attribute drift, feeding CPV and management review, and providing evidence at Batch Release/Finished Goods Release.

10) FAQ

Q1. Can we justify hold time using final product stability data?
Not reliably. Final product stability is necessary but not sufficient. Intermediates may be less protected (no preservatives, different headspace) and can drift faster. Perform targeted HTS on the intermediate.

Q2. Do we need a separate HTS for every batch size?
Use risk-based bracketing. If surface-to-volume and mixing regimes are comparable and worst-case (largest or smallest vessel) is validated, you may justify coverage for others—document the rationale.

Q3. What if we exceed MAHT during a breakdown?
Stop, segregate, and open a Deviation / NC. Perform risk assessment (attributes, micro), consider re-processing or rejection, and document QA disposition before resuming.

Q4. How are temperatures controlled and recorded during holds?
Through qualified sensors and data capture integrated to the eBMR; alarms should be tuned with SPC awareness to avoid nuisance.

Q5. Are cleaned components’ storage times part of HTS?
Yes. Post-cleaning hold time before use can affect micro risk; include it and link to Cleaning Validation and EM.

Related Reading
• Execution & Records: eMMR | eBMR | Audit Trail (GxP) | Data Integrity (ALCOA+)
• Risk & Validation: CPV | CAPA | IQ/OQ/PQ | Cleaning Validation
• Materials & Movement: FEFO | Bin / Location Management | Finished Goods Release | Batch Release
• Labels & IDs: GS1 / GTIN | Barcode Validation | Expiration & Shelf-Life Control