Detailed Analysis of the PIC/S Document 'Recommendations on Qualification and Validation' - Part II

Since September 2007, the PIC/S document PI 006 has been available in Version 3 ("Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation"). The revised Version 4 ("Recommendations on Qualification and Validation") will come into force on 1 October 2026 and significantly expands both its scope and level of detail. What is new? Part II below describes the changes from Version 4 compared with Version 3 regarding Process Validation, other Qualification and Validation topics and Cleaning Validation.

Process Validation

Process validation is no longer limited to non-sterile dosage forms. Version 4 explicitly positions itself as "state of the art" and refers to modern development and validation approaches, including QbD, hybrid approaches in accordance with ICH Q8 and the design space concept. The objective remains a process in a state of control; intra- and inter-batch variability should be controlled within the specifications. Bracketing is possible, provided that it is justified on a knowledge- and risk-based basis.

A minimum number of validation batches is no longer specified; the number must be scientifically justified. Challenge tests are generally not recommended, but may be used within normal specification limits to identify gaps in the risk assessment. PQ and process validation may still be combined, although attention is drawn to the different references involved - the URS for PQ and batch documentation for process validation.

Version 4 explicitly warns against distortions in the results caused by excessive sampling in relation to process variation. It therefore recommends scientifically justified sampling designs, using appropriate ISO standards, as well as the involvement of SMEs and statisticians (!).

With regard to the validation protocol, Annex 15 is cited as the basis, supplemented by additional points. Of particular note is the requirement in the revised version for a traceability matrix that demonstrates how the results of risk assessments have been transferred into the validation protocol.

Ongoing Process Verification as Part of the Process Validation Lifecycle

Ongoing process verification (OPV/Continued Process Verification/CPV) has been newly introduced in Version 4 as a lifecycle element following initial validation. It should be based on a risk-based monitoring programme and should regularly result in reports which, as a rule, cover no more than a one-year period. Any exceptions must be justified.

Where possible, objective statistical evaluations, such as Cpk/Ppk values, should be used and the metrics should be aligned to the required confidence in conclusion. "Legacy processes" which had been validated according to previous standards
should meet current process validation standards (gap analysis) and and should be incorporated into OPV programmes.

Routine revalidation is generally replaced by OPV. However, process changes must be assessed on a risk-based basis to determine whether revalidation is required. The scope of any revalidation may be reduced according a risk assessment compared with that of the initial validation.

It is also noteworthy that the deliberate omission of a fixed number of batches is justified on the grounds that this should promote scientific approaches and Quality Risk Management (QRM), including with regard to possible future developments of Annex 15 in this direction.

Other Qualification and Validation Topics

Transport verification, packaging validation for solid dosage forms, utility systems and analytical test methods are addressed as additional qualification and validation topics on a risk-based basis.

The subsection on transport verification covers, among other things, defined routes, reports in the event of deviations, the use of data loggers and sampling.

For packaging validation, critical process parameters must be identified through a risk assessment; a blister process is given as a practical example.

Utility systems with a direct impact on product quality should be qualified according to the same principles as other systems, supplemented by specific PQ aspects. Examples are provided for water, electricity, steam, inert gases and compressed air.

For analytical methods, reference is made to relevant guidelines, such as ICH Q2 (R2), FDA and WHO guidelines.

Cleaning Validation

Cleaning validation is described with a strong focus on scientifically justified limits, such as MACO and HBEL values, and on risk-based determinations.

Non-product-contact surfaces must be assessed from a risk perspective to determine whether they could nevertheless contribute to cross-contamination.

Version 4 contains numerous detailed requirements concerning the consistency of manual and automated cleaning, planning - including the contents of the cleaning validation protocol - roles and approvals, personnel training, equipment dedication and microbiological aspects.

"Visual inspection" is addressed separately. As part of validation, "visibly clean" should be supplemented by direct or indirect sampling followed by validated analytical testing. In routine operations, "visibly clean" may constitute a limit; however, this is not sufficient for products with a low HBEL or values close to the safety threshold.

Where possible, swab sampling is preferred to rinse sampling. Recovery studies are recommended for both approaches.

For limits, reference is made to PI 046. Historical criteria, such as 10 ppm and 1/1,000 of the minimum therapeutic dose, have been removed. Alert limits may nevertheless be based on historical or statistical evaluations.

A continued cleaning verification, reasons for revalidation and the justification of dirty and clean hold times are also addressed.

The glossary has been expanded to include several terms. The term "commissioning" has been removed.

Conclusion

Version 4 of the PIC/S document "Recommendations on Qualification and Validation" is considerably more comprehensive than Version 3. Many of the changes represent adaptations to the current state of the art.

Validation and qualification lifecycles are now required. The application of Quality Risk Management runs throughout the entire document. Statistical tools are consistently required wherever possible, and data integrity has gained considerable importance in all qualification and validation activities.

Terms from US regulatory frameworks, such as SME and PPQ, have also been incorporated. Alternative qualification approaches are identified, including ASTM 2500.

The level of detail is extensive in some areas and is supplemented by individual practical examples. This can certainly be helpful, but in some respects the document goes significantly beyond Annex 15 - for example, with the requirement for a statistician.

You can find Version 4 on the PIC/S website.