1-2 October 2019
In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 "Revision of the EU GMP Annex 15 for Qualification and Validation published"). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 "Detailed Analysis of Annex 15 Draft". Now the draft was published as final document and will be valid as of 1 October 2015.
What will change? Following you will find an overview about the changes.
With 16 pages the document is much more comprehensive than the current version (11 pages). In the section "principles" it is stated that the new EU GMP Annex 15 may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II"
Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process, whether with regard to equipment and the process validation itself. A special emphasis is on risk management which is mentioned in several sections in the guideline instead of being mentioned in one section only on risk assessment.
The new Annex 15 now specifically excludes a retrospective validation.
Validation Master Plan
The content of the validation master plan (VMP) has been extended. Deviation management is also supposed to be described in the VMP in the future, just as well as the standards for the development of acceptance criteria and the organisational structure. Compared to the draft version the mention of an "ongoing validation strategy" has been deleted. The request for naming the resources has also been omitted compared to the draft.
The possibility to combine qualification documents (e.g. IQ and OQ as IOQ) is explicitly mentioned. It is also foreseen to include manufacturer documents. Fortunately there is the possibility of conditional releases in the area of qualification. The final document contains a requirement to establish user requirements and/or functional specifications as a starting point of a qualification. The DQ is now the second step in a qualification. Additional new requirements are the Factory Acceptance Test (FAT) and the Site Acceptance Test (SAT). Especially for equipment with new or complex technology a FAT "may" be conducted. Compared to the draft this is a less strict requirement. In the draft document it was stated that a FAT "should" be conducted. If appropriate and assessed, tests and documentation reviews as part of the FAT can be taken over in other steps without repeating them in the IQ/OQ. This is a very helpful definition.
With regard to the PQ it is now also explicitly mentioned that (in certain cases) it can be combined with the OQ or the process validation. In difference to the draft it is stated that IQ, OQ and PQ "should" be conducted.
The chapter "Requalification" is new. Unfortunately the sub-chapter on established (in-use) equipment qualification has been completely omitted.
The options with regard to process validation have been extended. The previous "traditional" approach is still mentioned as a possibility, though - also with the determination of 3 validation batches. For a 3 batch validation further data from following batches may be necessary according to an "ongoing process verification". The possibility of a "continuous process verification" as described in ICH Q8, and a hybrid approach as a mix of the before mentioned two approaches is new. This is a clear difference to the US FDA Process Validation Guidance where only one approach is mentioned. According to the final EU GMP Annex 15 a "bracketing" approach can be used with respect to the number of runs, strength, batch size, packaging sizes and types. This is already known from the US.
As part of the "ongoing process verification" the product quality should be monitored during the product life cycle to show that the "state of control" is fulfilled and that trends are assessed. This is also known as "Continued Process Verification" from the US. The "ongoing process verification" should be based and reported according to a protocol or equivalent documents, latter is new compared to the draft. Completely omitted has been the subject of a (regular) revalidation.
The chapters "Transport Verification", "Packaging Validation" and "Qualification of Utilities" as well as a separate chapter on "Validation of Analytical Methods" are new. Compared to the draft the new final document now addresses also the qualification of equipment for secondary packaging.
The chapter Cleaning Validation comprises clear changes. The number of subitems is more than double now. Fortunately it is possible now to group equipment if this grouping is justified accordingly. The acceptance criterion "visibly clean" as single acceptance criterion is designated as not acceptable. Limits for the carryover of contaminations are supposed to be based on a toxicological evaluation. There is a reference to the EMA Guideline on Shared Facilities (see GMP News from 21 November 2014 "Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits (PDEs)". The so far common acceptance criteria 1/1000-Dose or 10 ppm are not mentioned. As part of the cleaning validation "dirty und clean-hold times" should be defined. The request from the draft to use the last rinse water as a sample in the application of rinsing methods has been omitted. Recovery rates should be determined. Interestingly the number of validation runs is supposed to be determined risk based. When producing clinical trial samples a cleaning verification could replace a cleaning validation.
In the chapter Change Control it is defined that an efficiency control is supposed to follow a change. This is an adaption to chapter 1, part I of the EU GMP Guide.
The glossary contains new terms.
The revision is quite comprehensive. Influences from the ICH Guides ICH Q8, Q9 and Q10 can be clearly noticed. This makes the document more modern, and it is more adapted to the current state of science and technology. The addressing of API manufacturer is somewhat irritating. Although the new Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs. But how is that supposed to work?
The statement that Process Validation is a life cycle is comparable to the FDA view.
The clear focus on user requirements in the area of qualification will also have an impact on equipment suppliers. Process validation will become a difficult task in the future. With 3 different approaches there are clear differences to the US. However, the ongoing process verification means additional effort and is now comparable to the US requirements.
Transport verification, the qualification of utilities as well as the validation of analytical methods are not new in the GMP enviroment. However, the topic packaging validation was not the main focus so far. This probably means additional effort for some companies.
The new Annex will result in considerable changes in the area of cleaning validation. A lot has fortunately been adapted to the current state of technology. However, the strong focus on toxicological evaluations as acceptance criteria with regard to existing products will certainly cause uncertainties.
Altogether there are plenty of new requirements which, however, partly only show the state of technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the FDA Guideline on process validation would have been desirable.
Please find the new EU GMP Annex 15 on the EU Commission Webpage
The new EU GMP Annex 15 will be covered at two ECA events. On 22/23 April the ECA offers the seminar "The new FDA/EU Approach to Process Validation" in Hamburg. And, at the 6th European GMP Conference on 9/10 June in Heidelberg the EU GMP Annex and the consequences will be discussed in a dedicated session.