Technical Review Article | Open Access | Published 13th December 2024
What is meant by pharmaceutical validation? A sprint through the Validation Master Plan
Tim Sandle, Ph.D., CBiol, FIScT | EJPPS | 294 (2024) | Click to download pdf
Validation is a well-established concept in the pharmaceutical manufacturing industry. One of the early definitions used by the US FDA still holds true, presenting the validation concept as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes” (as per ICH Q7).
What are the elements for ‘validation’?
However, it is useful to look at the key words in a little more detail.
Documented evidence: validation is an activity which must be recorded and be formally documented for inspection. To some extent this requirement often overwhelms the fundamental purpose of validation which is to demonstrate that a company has sufficient understanding of its processes to be able to operate them within limits which consistently meet their intended purpose.
Validation should be a technical discipline, not an overly bureaucratic one.
Consistently: a process which cannot be shown to be capable of performing consistently in the manner intended is of little value to manufacturing. One of the tenets of validation is that before a process is released for routine manufacture, it should have been shown through a sufficient number of replicate trials that it is capable of performing consistently.
This is not only regulatory sense, but it also makes business sense. Who would sensibly risk the costs of starting materials, labour, energy, packaging components without first being very sure that the output was not going to be rejected? Traditionally, consistency has been accepted by the regulatory bodies as something which has been demonstrated by three consecutive successful trials. This is a misnomer, for three successful trials is simply the minimum acceptable demonstration of consistency applicable only to low risk, well-understood processes.
Pre-determined: the expression pre-determined when applied to specifications and quality attributes indicates that validation is a confirmatory exercise and not an exploratory one. The exploration involved in new manufacturing processes belongs with the concept of “development.”
Under development it can be determination of what works (and preferably why it works), what its bounding limits (parameters) may be, and even process optimization, but this is not validation. Validation follows only when the limits have been pre-determined. Validation is therefore confirmatory.
There is also a requirement that all validation activities be planned. Validation encompasses numerous activities and qualifications which are independent yet interdependent of one another.
The world of pharmaceuticals. Image designed by Tim Sandle.
Structuring validation
In principle all validations are structured in the same way, there are a series of qualifications which must take place sequentially; each qualification must be completed and signed off before the subsequent one is allowed to begin, and all must be completed and in place before the final validation can be approved and the process released for routine use. Each qualification comprises a protocol pre-determined and approved before the work is allowed to begin, reflected by a report on which the actual results obtained are recorded. The concept of sequential qualifications has been established, each comprising a protocol and its corresponding report being visualized through something called a V-model. Under this model, validation comprises:
A series of qualifications which must take place sequentially – the cross bars of the V, A or the rungs of the ladder.
Each qualification must be comprised of a protocol which must be approved before the work can commence (this is the proof of pre-determination) and a report which contains the actual data obtained in implementing the protocol – the ties which hold the cross bars to the V (or A), or the ties which hold the rungs to the side-arms of the ladder.
The qualifications must be organized through a Validation Master Plan (VMP) which defines the sequence of qualifications etc. and states clearly where the actual program may differ from the “theoretical” program, and, importantly, why the validation is being done in a particular way.
What is required for the Validation Master Plan?
The VMP is a management tool. It enables management to organize information and check progress. The VMP must be a “living” document, one revised subject to new information which may not have been predicted or predictable. VMP’s should only be revised with the approval of the Quality function. VMP’s do not contain milestones and key completion dates in the way that project plans always do. Time for completion of validation is something which should be allowed for within every project plan, but validation comprises only a small part of any project plan. Some of the key elements in a VMP are:
Application and Scope. The VMP must describe unambiguously what is being validated (the application) and the scope of the validation. For instance, it might be that the application is validation of blending for a particular tablet product, using a specific blender located in a particular blending room (the scope). It may be that the blender has been in previous use in that location and some qualifications have been already done in connection with other validations. In such a case some, but not all, qualifications may not need to be repeated but may merely be referenced. On the other hand, it may be that the qualifications done previously need to be re-examined and updated. The definition of these activities belongs in the VMP.
Qualifications. In some instances, it may be practical to combine qualifications and if this is the case it should be stated in the VMP. It is universally the case that all new processes are prospectively validated (that is, all qualifications must be complete before the process is released for routine use) but there may be items of equipment or services (e.g. steam generators, compressors etc.) identified when preparing the VMP that have not been previously qualified. If this is the case, their retrospective qualification should be included in the VMP and referenced to the company’s policy which allows this.
Standards. The VMP is not the place for detailing the standards and limits being applied, this would merely amount to a repetition of detail necessarily included in the qualification protocols. However, it is important to state which standards are being applied (USP. Ph Eur, ISO, EN etc.) There may be other local legislative or insurance requirements that place restrictions on how equipment is used or how processes are run which should be included in the VMP.
Deviations. Qualifications should be performed in sequence, each one completed and approved before the next one begins. It sometimes happens that the completion and formal approval of a qualification is delayed because of something quite trivial such as a key signatory being absent through illness, a metallurgy certificate being delayed in the post. It is not good business sense and is indeed mindless bureaucracy to delay moving to the next qualification for such reasons. However, if progress to the next qualification is going to be allowed, there should be a mechanism for documenting and obtaining approval for it contained in the VMP. There should also be some assurance that any such deviations should be addressed and signed off before the validation itself is allowed to be completed.
Disposition of Materials. The VMP should define if product (or intermediates) manufactured as part of validation trials may be released to market, and under what conditions this might be possible.
Revalidation. Validation does not stop with the final sign off on the VMP. The philosophy of validation is that it continues through the “life cycle” of an item of equipment or a process. Validity should at the very least be reviewed periodically (Validation Review) through scrutiny of equipment logs, maintenance records, deviations, out-of-specifications and Periodic Product Quality Review reports (PQR in EU, APR in USA) to determine if the equipment or process is still operating consistently to the same pre-determined specifications and quality attributes. If not there may be some further requirement for process development or equipment modification or even withdrawal from use. The frequency for formal Validation Review should be defined in the VMP. Often “re-validation” in the sense of repeating some aspect of the original validation (usually Performance or Process Qualification) is only required in the event of a significant change, or from something highlighted in Validation Review. However, there are some processes and items of equipment (notably sterilization processes, autoclaves, ovens, tunnels etc.) which require a regular periodic re-qualification. Mostly the processes requiring re-validation have been identified by the regulatory authorities either in guidance documents or through custom and practice at inspection. They have been determined from risk analysis (probably intuitively rather than by formal risk analysis) and are largely in those areas where serious patient risk could arise from undetected or undetectable “slippage” in the performance of a piece of equipment or a process.
Responsibilities. Validation is a team effort. The VMP is where the composition of the team is defined, and the responsibilities of each team member. Where equipment is being qualified it may not be clear what should be done by Engineering staff and what should be done by Production staff, it may not be clear if samples are to be collected by Quality staff or staff from some other function. The time to argue these points and make these decisions is in preparation of the VMP, it minimizes confusion at more critical times. The function responsible for preparing protocols and for filing protocols and completed reports to form the validation dossier should be defined in the VMP. Finally, the list of signatories required for each stage of approval should be defined in the VMP; modern thought is to minimize this list as large numbers of signatories delay approval and dilute responsibility.
Representing the world of microbiology. Designed by Tim Sandle.
Microbiology
Potentially, pharmaceutical microbiology could be involved in all validations. This includes the design of new facilities (and modification of existing facilities). Hygiene is a critical quality of all pharmaceutical manufacturing facilities, not just those dedicated to manufacture of sterile products. Another area is with the installation of new water systems (and modification of existing water systems). Microbiological problems are almost inevitable except where high temperature storage and distribution systems have been installed. There is also the installation of new thermal sterilization processes and the introduction of new processes involving bacteria-retentive filtration and process qualification of all products with a significant water content, among other key areas.
Tim Sandle is the author of the book Sterility, Sterilisation and Sterility Assurance for Pharmaceuticals: Technology, Validation and Current Regulations.
Author Information
Corresponding Author: Tim Sandle, Head of Microbiology
Bio Products Laboratory,
UK Operations,
England
Email: timsandle@btinternet.com
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