16-17 October 2019
At the end of 2015, the WHO adapted its Appendix 7 to the latest technological standards. Appendix 7 provides support with regard to non-sterile process validation. Now, further changes to WHO guidelines are in sight. One of these changes concerns the guideline on process validation which is currently available as a draft and can be commented on until July, 12th 2016. Please find here an analysis of this draft.
The draft contains 21 pages divided into 13 chapters and one part with references.
The guideline serves as a sort of umbrella guideline and should replace in the future Annex 4 of the WHO Technical Report Series No. 937 from 2006. In so far, the draft refers to other guidelines about the topic validation which will thus have to be updated too as subordinated guidelines (Appendices). The following appendices are named:
Appendix 1 Validation of HVAC systems (currently already available as a revised draft)
Appendix 2 Validation of water systems for pharmaceutical use (will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical use for consideration in qualification of water purification systems)
The introduction describes validation as an essential part of GMP and GCP. Validation also includes qualification and a lifecycle comprising an "ongoing review" for continuous improvements. The necessity, scope and depth of validation activities should be based on quality risk management principles.
The following resources are listed:
The chapter “Scope“ points out that the draft describes an overall validation concept which could be applicable to the manufacture and control of starting materials and finished pharmaceutical products. The qualification aspects included in the document could also apply to premises, equipment, utilities and systems.
Made up of three pages, the glossary is very extensive. It is interesting to see that this chapter offers a definition for the terms "Commissioning" and “Good Engineering Practice”. The definition for process validation is very close to that of the FDA. Performance qualification is described as applicable to equipment and systems. In the context of systems, the term “process validation” could also be used. There is also a own definition for the term “validation“ (“Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results”). The term “retrospective validation“ is not listed but the term “revalidation“ - also in the sense of a periodic (re)validation.
Chapter 4 addresses the relationship between validation and qualification. “Qualification and validation are essentially the same” whereby qualification is normally used in relation to equipment and utilities, and validation in relation to systems and processes.
Chapter 5 “Validation” and its subchapter “Approaches to validation” include some interesting requirements. Where appropriate, statistical calculations should be used to deliver the scientific proof that the process, systems and other related aspects are appropriately validated. Moreover, the senior management is explicitly spoken to with respect to the availability of resources. Both the management and the persons responsible for quality assurance should be actively involved in the validation activities as well as in the authorization of protocols and reports. Regarding the topic risk management which should be used, it is referred to a specific WHO guideline. Where necessary, worst-case tests or so-called "challenge tests" should be performed like for example stress load tests and volume verification tests in computer systems.
The documents needed to accompany the validation activities (Chapter 6) include among other things protocols and reports as well as a validation master plan. By means of own (superordinate?) plans, it should be ensured that a validation review is available which guarantees the maintenance of the validated status. The next chapters look at the validation master plan, protocols and reports.
A validation master plan – concise and clear - should be available (Chapter 7). However, 28 minimum requirements are listed. One should notice that this high number is mainly due to the fact that for the qualification activities each sub item is respectively listed for the qualification of premises, equipment, utilities. The same applies to the validation activities (cleaning, process, analytical methods, and computerised systems). The validation master plan should be regularly reviewed and the GMP status should be kept up-to-date.
The minimum requirements concerning the validation and qualification protocols are fairly detailed too (15 items). Chapter 8 also points out that there should be a description of how results should be analysed (including statistical analyses where appropriate).
Also in the following Chapter 9 on qualification and validation reports, the focus of reporting is put on statistical analyses where possible. The final approval of reports should be done by the quality assurance department.
Chapter 10 Qualification
Made up of almost 3.5 pages, Chapter 10 (Qualification) is relatively extensive. It suggests that there are different approaches to qualification. The V-Model for Direct Impact Systems is given as an example. Yet, the model presents abbreviations which are not explained (e.g. UAT). “Normally” – quoting the text – „qualification should be completed before process validation is performed”. "Normally", qualification should begin with user requirement specifications (URS). Depending on the object considered, the following steps are: FAT, SAT, DQ, IQ, OQ, PQ. According to the document though, major equipment and critical systems may require at least URS, DQ, IQ, OQ, PQ. Now, there may be some equipment which only requires IQ and OQ when those two qualification stages already indicate the performance of the equipment. It is explicitly mentioned that a qualification stage should be completed before the next one can start. An own paragraph addresses computerised systems requiring user and functional requirements specifications, design and configuration specifications. Stress tests are also required for those systems. Apart from that, it is referred to the respective WHO on computerised system validation. Not as clearly as in Annex 15, it is pointed out that the URS should be the starting point for the next qualification stages. Each qualification stage FAT, SAT, DQ, IQ, OQ, PQ is then addressed whereby FAT and SAT are listed as “should be” provisions where appropriate. In the course of OQ, worst-case studies are required and when measurements are made with a statistical approach, they should be described. Test results and continuous process verification (continued process verification is likely to be meant) should be collected over an appropriate period of time and /or within periodic reviews and monitoring to demonstrate that the equipment operates consistently.
The subchapter “Requalification” expressly mentions that full requalification is not required for the replacement of parts but a "like for like" replacement. Where items of equipment haven’t been used for a longer period of time, requalification may have to be considered.
Another subchapter on revalidation points out that where periodic revalidation is performed, this should be done within defined cycles. Periodic revalidation should be considered when small process changes occur over a longer period of time. The frequency and extent of revalidation should be determined on a risk-based approach taking into account historical data.
Within one paragraph only, the subchapter “Process validation” addresses the new approach and lapidary refers to other process validation guidelines. Another paragraph is dedicated to the traditional process validation and expressly underlines the necessity of validation when applying the traditional approach (e.g. through product quality reviews).
Chapter 11 and 12
The contents of Chapter 11 (Change Management – only 3 paragraphs) and Chapter 12 (Deviation Management, just one paragraph) are relatively low compared to Chapter 13 on calibration and verification which is considerably more extensive (one page). Here, the text highlights the necessity of regular calibration with traceable calibrated measuring devices. IQ is considered as appropriate qualification stage for calibration and verification of equipment. Whether devices or instruments should be calibrated should be based on an impact or risk assessment.
Although this guideline has been thought as superordinate guideline for other validation and qualification guidelines, it has – in its current draft status – relatively little relation to the validation lifecycle approach as required in Annex 15 and FDA’s process validation guideline. There are no references to development which represents the basis for a modern validation approach. Still, periodic revalidation is basically required. Interestingly, references to the application of statistical methods – where appropriate – recur again and again. Another interesting aspect is the mention of “GEP” and “Commissioning“ in the glossary whereby no further explanation is given as for the V-Model. In the course of qualification tests, conditional approvals (as mentioned in Annex 15) are not intended. The specification according to which a "like for like" replacement requires requalification is very interesting. This is a contrast to PIC/S’s document “PI 006-3, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation” in which a "like-for-like" replacement normally doesn’t require requalification. All in all, a closer alignment with other process validation guidelines would be preferable.
The draft can be commented on until July, 12th 2016. Delegates and former delegates of ECA events as well as ECA members have access to the Members Area where the draft of WHO Guidelines on Validation can be downloaded.