The revised PIC/S guideline on qualification and validation completely updates many key activities typical of pharmaceutical manufacturing to the latest advancements in science, technology and regulatory acceptance. The new guideline has entered into force on 1 October 2026
Qualification and validation (Q&V) are key activities in the daily work of industrial pharmacists, as they directly affect the setup and routine operation of many manufacturing and quality assurance processes, including equipment qualification and process and/or cleaning validation. Basic principles for Q&V activities are addressed in Annex 15 to the European Good Manufacturing Practices (GMPs). The application of the Annex is supported by the recommendations detailed in the newly revised PIC/S guideline on qualification and validation, which entered into force on 1 October 2026 (PI006-4).
https://picscheme.org/en/news/revision-of-pics-recommendations-on-qualification-and-valida
Drafted by PIC/S’ dedicated working group, the new release completely replaces the previous
version PI006-3, published in 2007. The original guideline dates back to 1998; today’s revision
reflects the latest advancements in pharmaceutical manufacturing, following the 2015 update of Annex 15. The revised version will support training for GMP inspectors and help the pharmaceutical industry in developing new GMP-compliant processes. The new PIC/S PI006-4 guideline applies to pharmaceutical active substances, intermediates, and finished dosage forms. It does not address validation of computer systems (covered in Annex 11), nor the validation of in-depth analytical test methods or aseptic processes.
Three key principles
Qualification and validation activities aim to provide the documentary evidence needed for the management of medicine’s lifecycle, also from the regulatory point of view. Particular attention should be paid to validation of control strategies and manufacturing processes to reduce potential sources of variability in the final quality of the product. According to the new PI006-4 guideline, Q&V should follow a lifecycle- and data-governance-based, risk-based approach and be continuously monitored and updated to incorporate the latest improvements to processes. Senior management is called to understand the impact of these processes and provide the necessary resources. Manufacturers are free to choose how to address validation and qualification, based on the provision of documentary evidence of the detailed processes understanding and product knowledge. If contractors or consultants are involved, the contract giver retains final responsibility for the overall Q&V process.
Change control should represent the starting point of qualification, a central concept that
should be reflected in high-level documents such as the Quality Manual or the Validation Master
Plan (VMP). The potential impact of changes should always be evaluated using Quality Risk Management, so so as to better plan the needed qualification and validation activities. The PIC/S guideline also addresses change control for complex projects, which can be initiated at a child level and approved at an appropriate level, including the involved departments, the Quality Unit, and the change control board. Evaluation of planned actions should be based on
measurable metrics, while multiple failures to meet the approved implementation timelines
may indicate a lack of control or inadequate resources.
The Validation Master Plan
The VMP is the key summary document detailing the manufacturer’s approach to qualification
and validation. It should provide an overview of the entire Q&V dimension, including a list of the
involved facilities, utilities, systems and processes. A schedule for completion and lifecycle
review of the state of control should also be provided. According to the new PIC/s guideline, a
merely descriptive VMP will not meet the inspectors’ expectations.
A main improvement of the new version is the clarification that the worst-case approach should
not be used to validate “to the edge of failure”, but to confirm the process’ robustness across
normal process variation. Rationale should also be provided to support challenges, “worst-case” situations, or grouping of products/processes.
As for deviations, they may refer to failure in meeting the fixed acceptance criteria, as well as
to the protocol not being executed as specified. Deviations should be recorded not only in the Q&V report, but they should also be visible in the site’s deviations system to support later investigations into the failures. The new guideline also specifies that personnel other than the one who executed the work should independently confirm data integrity in Q&V reports.
Qualification of facilities, utilities, equipment and systems
While the new PI006-4 guideline retains the already established approach to qualification, i.e. setting of User Requirements Specifications (URS) followed by design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ), it also acknowledges the possibility to use different approaches based on good scientific or engineering practices (i.e. the ASTM E2500 standard).
The guideline specifies that conditional approval to proceed to the next qualification stages is
possible if certain acceptance criteria are not met or deviations occur, provided documentary
evidence shows the impact on the next activity is not significant. Factory Acceptance Testing (FAT) run at the supplier site for some systems, or Site Acceptance Testing (SAT) may be used to reduce the IQ/OQ scope, upon provision of appropriate justification and reference to approved protocols and reports.
Deviations identified in the pre-qualification and qualification activities should be addressed through appropriate CAPAs before the involved facilities/equipment/systems can be considered fit-for-purpose. For re-qualification activities, the guideline specifies that “like-for-like” changes can be handled within the planned preventative maintenance system upon justification, Quality Unit approval, and documentation of the relevant decision.
Process validation
The new lifecycle approach makes validation no longer a one-time activity. According to the new PIC/S guideline,retrospective process validation is no longer acceptable; therefore, legacy processes should be revalidated to meet current expectations based on a new cap analysis and risk assessment. All process validation activities should aim at demonstrating the establishment and maintenance of a state of control.
Indications of the PIC/S guideline do not refer to specific product types and may also be applied to the manufacture of investigational medicinal products. Process design can be traditional, based on the quality-by-design approach, or a hybrid of the two, and should be considered an integral part of process validation, together with the associated routine control strategy.
Information on development studies should be available at the manufacturing site prior to the formal start of process validation. Under the prospective validation approach, the initial validation of the commercial-scale process should be completed before manufacturing of batches intended for sale. A list of 12 prerequisites to be met before commencing validation of a commercial manufacturing process is also provided in the guideline.
The revised PIC/S guideline also discusses concurrent validation, which can be used in exceptional cases to run validation protocols simultaneously with the commercialisation of process-validation batches. Furthermore, batches manufactured for process validation should have the same size as commercial scale batches. Bracketing would also be acceptable only if based on solid scientific design and upon compliance with risk management principles. Challenge testing should be avoided and is considered acceptable only to close remaining minor gaps arising from the risk assessment.
According to the guideline, there is no longer a need for three validation batches: the actual number of batch replicates should be decided by the manufacturer on the basis of robust process and product knowledge and demonstrable control. The document also acknowledges that in some cases it is not possible to distinguish between PQ of facilities/equipment and validation of the manufacturing process. In such instances, all the relevant PIC/S GMP Annex 15 requirements should be met.
Cleaning validation
Central to the PIC/S guidelines chapter on cleaning validation is, once again, a documented quality risk management approach, with validation being part of the contamination control strategy.
Cleaning procedures should aim to remove residues (microbial, product-related, or from cleaning agents) to levels below the scientifically determined maximum allowable carry-over (MACO) value. If manual cleaning is not a valid option because products have low health-based exposure limits (HBEL), automation, dedicated parts, or verification at every changeover should be considered.
The guidelines also describe how to articulate cleaning verification studies (to be initiated in parallel with the start of commercial production, or during development, provided the cleaning process is fully defined) and cleaning validation programs. Requirements should be established based on a documented quality risk management assessment. The extent of the cleaning program should also reflect the toxicological risk assessment performed on the specific product/process.
Depending on the product risk, it may be acceptable to conduct cleaning validation studies on a limited number of (multiple) worst-case products, provided there is documented justification for this approach. Furthermore, cleaning validation should involve all equipment unless items are exact “like for like” or any differences are justified and practically confirmed to have no impact on the consistency of the cleaning procedures. The guideline also addresses factors that support consistency of manual or automated cleaning.
Starting materials from different suppliers should also be considered, as they may have different physical and impurity profiles and thus require a tailored cleaning-procedure design and validation. Continuing cleaning failures and/or “testing until clean” is expressly considered unacceptable. Intermittent cleaning failures would require appropriate remediation actions, and should be recorded and investigated for their impact on validation and verification.
The importance of transportation
A key upgrade of the PIC/S guide addresses the growing importance of maintaining appropriate storage and transport conditions throughout the supply chain, including intermediate and semi-finished products, APIs, and samples. Chapter 6 underlines that, in many cases, international and domestic shipments of pharmaceutical products may face unpredictable variables. A risk assessment of known variables (weather, customs delays, staff shortages, breakdowns, etc.) should therefore be performed, with inclusion of newly identified variables as soon as they emerge. Particular attention should be paid to the transportation route, which should be formally documented and verified before use by executing a test protocol.
Temperature, humidity, light, and vibration are examples of environmental factors to be considered in the risk assessment, along with the loading of the container to ensure adequate air circulation and prevention of mould formation.
Data loggers may be used to monitor actual shipments, with at least one data logger per pallet for air transportation; procedures for downloading data and ensuring their integrity should always be part of the shipping study protocol and verified before report approval. Pre-selected samples sent separately from the batch should be subject to the same transport conditions in order to be truly representative of the experienced environmental conditions.
The guideline also emphasises the importance of validating the packaging process, as any failure in the container integrity can significantly affect the product’s stability and overall quality.
