The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has revised its Recommendations on Qualification and Validation, issuing document PI 006-4. The updated recommendations entered into force on 1 October 2026, replacing the previous version, PI 006-3, which dated from 2007. The revision brings together and updates recommendations on validation master plans, installation and operational qualification, process validation and cleaning validation.

Scope and application

PIC/S announced the revision on 30 July 2026. The document is intended as guidance and a training resource for GMP inspectors and the pharmaceutical industry. Its principles apply to the manufacture of active pharmaceutical ingredients (APIs), intermediates and finished dosage forms.

PI 006-4 takes account of the 2015 revision of GMP Annex 15 and promotes a lifecycle approach to qualification and validation. The scope and documentation of activities should be proportionate to the relevant lifecycle stage, supported by scientific knowledge and documented risk assessment.

The recommendations do not replace specialised guidance on all validation topics. GMP-relevant computerised systems remain covered by PIC/S GMP Guide Annex 11, while aseptic process validation is addressed in the separate PIC/S document PI 007. Analytical test-method validation is included in PI 006-4 but is not covered in depth.

Lifecycle approach and risk management

The revised recommendations integrate qualification and validation into the pharmaceutical quality system. Activities should be reassessed as facilities, equipment, processes and technologies change. Data governance and data integrity should be considered throughout the lifecycle.

Quality risk management should determine the scope and extent of qualification and validation work, focusing on aspects most likely to affect product quality and patient health. Change control, deviation management and appropriate documentation remain essential.

The Validation Master Plan (VMP) should describe the manufacturer’s overall strategy and responsibilities. It should provide an overview of the facilities, utilities, equipment, systems and processes requiring qualification or validation, together with the relevant schedules, responsibilities, risk-based rationale, change control, deviation management and data-integrity arrangements.

PI 006-4 also recognises that alternative scientific and engineering approaches, including those based on ASTM E2500, may be appropriate where they demonstrate that facilities, utilities, equipment and systems are fit for their intended use.

Qualification: flexibility in the approach

The recommendations retain the established qualification stages of Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ), while providing greater scope for alternative approaches based on scientific and engineering principles.

Factory Acceptance Testing (FAT) and Site Acceptance Testing (SAT) may support qualification and, where justified, reduce the extent of subsequent qualification activities. The evidence and rationale must nevertheless demonstrate that the equipment or system meets its intended requirements and is suitable for use.

Process validation: retrospective validation is no longer acceptable

PI 006-4 explicitly states that retrospective validation is no longer an acceptable approach. Initial commercial-scale process validation would normally be expected to be completed before batches intended for sale are manufactured. Concurrent validation may be used in exceptional circumstances, with appropriate justification.

The number of validation batches should be based on scientific evidence, process understanding and demonstrated control rather than a fixed expectation. The recommendations address prospective and concurrent validation, as well as traditional, enhanced and hybrid approaches.

Manufacturers should also review processes validated under earlier standards and bring them into line with current expectations. This includes ongoing process verification (OPV) and any additional testing or controls identified through gap analysis and risk assessment. OPV reporting periods should be risk-based and would normally not exceed one year, although justified exceptions are possible.

Utilities, transportation and packaging

PI 006-4 adds or expands recommendations on supporting utilities, transportation verification, packaging validation for solid-dose products and test-method validation.

For water-system qualification, performance qualification would normally extend over a full year to assess seasonal variations in the water supply and their potential impact on the treatment system. Transportation routes should be documented and verified before use, with risk assessments addressing relevant environmental and logistical conditions.

Cleaning validation and continued process control

The revised cleaning-validation recommendations place particular emphasis on scientifically justified residue limits, including health-based exposure limits (HBELs) where applicable. Sampling methods should reflect the equipment design, residue characteristics and cleaning process. Swab sampling is generally considered more effective than rinse sampling and should be used where feasible.

Visual inspection remains an important part of cleaning assessment. It should be performed by appropriately qualified personnel under suitable conditions. Where residues cannot be detected visually below the relevant safety limit, cleaning verification may be required at every product changeover.

What manufacturers should review

Manufacturers should assess their existing qualification and validation programmes against PI 006-4, with particular attention to:

• Validation Master Plans: review the overall strategy, responsibilities, scope and lifecycle planning
• Qualification programmes: assess the use of URS, DQ, FAT, SAT, IQ, OQ and PQ, including scientifically justified alternative approaches
• Process validation: review prospective and concurrent validation arrangements, the rejection of retrospective validation and the implementation of ongoing process verification
• Data governance and risk management: ensure that data integrity, change control and documented risk assessments are integrated throughout qualification and validation activities
• Utilities and transportation: review qualification evidence, seasonal water-system performance and transport-route verification
• Cleaning validation: reassess residue limits, sampling strategies, visual inspection and changeover verification

PI 006-4 provides updated recommendations for inspectors and industry; it is not a standalone replacement for applicable GMP requirements. Manufacturers should therefore consider it alongside the relevant GMP guide and other applicable regulatory guidance when reviewing their quality systems and validation programmes.