This paper explains what European Annex 15 covers (excluding Cleaning Validation that is covered in other papers) and how it links to modern Process Validation (PV).
Note the regulatory authorities have said they expect to update Annex 15 -one assumes to align with the as yet unpublished final version of the EMA PV Guidance. (A draft was issued in Mar 2012 for comment by Oct 2012).
Annex 15 is entitled ‘Qualification and Validation’ and is laid out as follows:
Section 1 on Principles has one paragraph which in fact only mentions 3 Principles:
The remainder of Annex 15 covers the processes to be used i.e. VMP, DQ, IQ, OQ, PQ, see below.
It says that all validation activities should be planned. The key elements of a validation programme should be defined and documented in a validation master plan (VMP) or equivalent documents.
The VMP should be a summary document which is brief, concise and clear and contains data on at least the following:
Annex 15 defines the terms DQ, IQ, OQ, PQ and Process Validation as follows:
The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.
The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.
The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.
The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes
Regarding Process Validation it says that, “It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process.”
For documentation, Annex 15 says a protocol should be written specifying how validation and qualification will be carried out, specifying ‘critical steps’ and acceptance criteria.
It also covers the requirements of prospective, retrospective and concurrent validation (note these first two terms are not used in the FDA Guideline and the latter term is only referred to in regard to concurrent release).
Industry’s Historical Approach in Using Annex 15
Although Annex 15 doesn’t spell out the importance of product quality in Section 1, Principles, the topic is clearly there in the intent behind the processes that are to be used.
As a comment, maybe because this principle is not spelled out at the outset, plus the need to link to the patient requirements to process validation, historically the practice of validation has become bureaucratic and complex. Perhaps the explanation of this is:
The outcome was that a bureaucracy of validation built up, often run in parallel to other project management processes, where the emphasis on product quality became subservient to the administrative process itself. However, there were still some good ideas in the traditional approach, for example the V-model, as shown in the second diagram.
The traditional validation process is shown in the diagram below:
Industry used a ‘V model’ as shown below, starting with DQ and working through IQ, OQ, PQ etc and linked this to ‘specifications’ of various types. This normally meant, when a new plant was built, the first stage was to assess what was needed for Design Qualification (DQ), then IQ, OQ, PQ and finally when all the qualification was in place, process validation could start, i.e. the qualification steps followed the engineering procurement process.
Indeed, Process Validation, although it is the last item in the exercise (and probably the most important), it didn’t appear in the V diagram.
One other matter, the term ‘critical’ is used about 6 times in Annex 15 but the context of it varies, so this may have also added to the historical confusion. For the future, the use of ICH definitions that define the context of the word ‘critical’ and link it to product quality (e.g. Critical Quality Attributes or Critical Process Parameter) will help clarify what is important to validate and where validation can confirm that plants and manufacturing processes do deliver what is critical for patient safety and efficacy.
Applying Annex 15 and the Principles of FDA 3 Stage Process
Say a company wishes to adopt the principles of the FDA PV Guideline 2011 including use of ASTM E2500 for equipment and utility verification, then Annex 15 requirements, as illustrated in the diagram below, can still be met in order to supply EU markets. Here the FDA 3 stage approach is shown with an adapted V model inserted for Stage 2.1 (equipment and facility verification) that enables the ASTM E2500 process (i.e. reference to terms Requirements, Specification and Design, Verification and Acceptance and Release) to be used. Note ASTM also supports the principles of Good Engineering Practice, use of Subject Matter Experts, a science-and risk-based approach, design review and change management.
Regarding documentation, the Annex 15 requirements for DQ/IQ/OQ/PQ/PV can be drawn out of the overall 3 stage process by referring to documents generated by that 3 stage process. This could include reference to, for example, plans (such as User Requirement Specifications (URS)), protocols, verification tests and vendor documents, (such as Factory Acceptance Tests (FAT), Site Acceptance Tests (SAT)), reports, etc.
These documents also would be used to demonstrate that the validation process had confirmed a control strategy (using the term from ICHQ10) was in place and that the manufacturing process was able to deliver quality product.
So whereas historical validation under Annex 15 had proceeded along similar order of activities to engineering procurement for a new plant (i.e. Design, Install, Operate etc. viz DQ,OQ, IQ etc.) modern validation work shifts the sequence of activities for meeting Annex 15 requirements to the following, and so has an impact on how engineers will design plants to ensure product quality.
Compliance with Annex 15 can still be put in place using modern Process Validation principles but the administrative process shifts from a compliance-based approach, (using the terms DQ/IQ/OQ/PQ as the validation process and ‘proof’ of product quality being 3 batch validation) to a science- and risk-based approach to product quality, and it is this that drives the DQ/JQ/OQ/PQ/PV requirements, including necessary documentation.