Why Three Batches are Taken for Validation?

Neither the cGMP/ICH Q7 rules nor FDA policy requires a minimum number of batches for proving the validity of a process. The FDA considers a reduction to 3 batches as too simple for being able to prove validity. Yet, the regulatory admit that the idea of having 3 batches is widespread and can in part also be traced back to its own guidance documents. The number of 'validation batches' shall be determined on the basis of knowledge.

Once upon a time, processes validation finished by producing 3 good batches and from that basis claiming that the process is able to produce good quality. Today, authorities related to the Pharmaceutical industry do not consider 3 batches nor any other arbitrary number of batches as sufficient to validate a process unless statistically proven that it is sufficient.

Before reducing the level of sampling and monitoring to a routine level, Pharma Industry needs enough batches and samples to establish scientific proof with confidence that the process is reproducible and will consistently deliver quality products.

This is a common concept to validate three consecutive batches in pharmaceuticals. In process validation and cleaning validation, the initial three batches are taken for validation. This is a basic question that concentrates everyone’s mind why three batches are taken for validation?

Neither FDA nor any other regulation specifies the maximum number of batches to be considered as validation. The manufacturers have to choose the number of batches to be validated in this regard. The number of batches to be taken under validation depends upon the risk involved in the process of manufacturing.

What is Validation?
  • Validation is documented evidence that ensures that a process or procedure consistently produces a product with the same quality standards.
  • Validation has great importance in the pharmaceutical industry because for every product manufacturing we conduct a validation activity. This process validation gives us assurance that by using the defined process we can consistently get the same quality product.
  • Pharmaceutical validation is important to the manufacturing process to ensure product consistency and safety. It involves regulation of all raw materials and production procedures as well as testing of the final product. 

Key Benefits of Validation
There are several benefits of Validation in the pharmaceutical industry some of them are illustrated below:
  1. Validation of the process helps to find any big or small fault in the manufacturing process. That helps to be prepared to avoid such faults in the future.
  2. It helps to find any error or deviation in the process or system over time.
  3. Significant process parameters and controls can be determined during the validation of the process.
  4. The system and equipment can study thoroughly by the validation process.
  5. Validations make audits easy and comfortable by following steady processes.
  6. Process validation allows for minimizing the process control and product analysis requirement.
  7. Process validation reduces the quality difference between two or more batches.
  8. Validation reduces the wastage of materials during manufacturing processes.
  9. It reduces the reprocessing work and thus improves output production.
  10. Minimize the failure of any product at the finished stage of the product.

Why do we need Validation in Pharmaceutical Manufacturing?
  • We need validation in pharmaceutical manufacturing because the medicines we make must be of the same high quality every time we make them.
  • This high quality is important so that the medicine is safe for patients to take, will help to make them better, and will not harm them in any way (i.e. they’ll be fit for use and function as expected).
  • We can test final medicines at the end of the production process but final end product testing just isn’t enough.
  • Every time you test medicines you have less to give to patients. If you are just testing quality through final products, you have to test a lot of them.
  • However, if you can confirm that a medicine is safe to use every time you made it a certain way and that you made it the same way every time, it’s a reasonable assumption that the medicine you made this time (in the same way) is also safe for patients to use.
  • To be sure that the final medicine is safe and effective for patients to take, we also have to check in on it at multiple points along its way to becoming a final product (i.e. are the ingredients used and the “in-process” materials all the same as expected?).
  • We have to rigorously scrutinize the processes, systems, and equipment used throughout manufacturing.
  • We need to confirm that everything we did was the same as on other occasions when we produced safe medicines using this “validated process”.
  • At all points, validation tests are comparing a result against a predetermined specification (or an expected result range).
  • Only by looking at – and documenting – the whole manufacturing process in this way, can we say for sure that a final medicine will be safe and effective for patients to take. 

Homogeneity within a batch and consistency between batches are goals of process validation activities

  • Most medicines are made using a batch process. Basically, validation activities are making sure that everything in one batch is the same. But they’re also making sure that those things are the same as other batches manufactured by the same process.
  • We need much stricter control over the process. Therefore, consistency between batches is just as important an outcome of validation activities.
  • To achieve this, each step in the process can be subject to validation.

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Justification for 3 Batches
  • Is it just a scientific tradition behind the three? In any case, leaving this behind is symbolic of new work culture around process validation.
  • The Rule of thumb of three makes no difference how demanding the validation is: Is it a completely new process for a completely new product (e.g. production for a new vaccine), or is it just a product transfer, or the 200th validation for an in-house sterile filling process? It cannot make sense to apply the same effort to validation batches in all cases!
  • There is another saying as well for the 3 batches. If one batch meets the quality requirement, it is an "Incidence", if two consecutive batches meet the quality requirement, it is a "Coincidence". But, if three consecutive batches meet the quality requirement, it is "Consistent".

What are the authorities demanding?
  • According to the FDA and EMA, in traditional validation, 3 batches may be sufficient for comprehensive validation. The required number of batches should be derived from the risk analysis. In particular, the FDA requires that not only is the process be validated but also the process performance. 
  • Today, there is an actual statistical rationale for only a few process validations. Many companies still work with the golden 3 batches. But approaches to statistical, risk-based determination of sample size for validation batches are evolving. This is especially the case when the cost of active ingredients is high or the time for development is short.
  • Especially for the identification of risks, overarching cooperation between R&D, dossier development, QA, QC, supply chain, and production is essential. Only in this way can those likely unconsidered risks arising from process steps also be identified.
  • Neither the cGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. The current FDA guidance on APIs also does not specify a specific number of batches for process validation. 
  • FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full-scale batches
  • FDA's process validation guidance now recommends a product lifecycle approach. The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected.
  • However, a minimum number of validation batches necessary to validate the manufacturing processes is not specified. The manufacturer is expected to have a sound rationale for its choices in this regard. The authorities encourages the use of science-based approaches to process validation.

How many batches are recommended in the validation of process?
  • The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful productions batches should be used as a guide, but there may be situations where the additional process runs are warranted to prove the consistency of the process".
  • The number of batches required to validate a process will depend on the company’s process understanding, as well as on the type and variability of the process. “Validation with fewer than three batches will require good statistical and scientific justification,. The less documented knowledge there is about a process, the greater the number of validation batches that will be required.”

Why not less than 3 Batches?
  • For affirmation of reproducibility and to show the consistency, we must have sufficient numbers of batches to evaluate batch to batch variations. If we pick 2 batches for validation then we cannot evaluate the statistics of batches due to the fact contrast among points always gives a linear line so to reveal the difference we want three points. So typically we take three or greater than three batches for validation.

Why not More than 3 Batches?
  • As we understand currently there aren't any guidelines available for choosing the minimal or a maximum range of batches so we also can take four or 5 batches. because the wide variety of batches is multiplied the cost of the process and time required is extended so all pharmaceutical companies typically select three batches for validation.

Until now, the industry has adhered to the tradition of producing three batches of products to validate its manufacturing processes. But FDA's new process validation guidance does not prescribe any number of batches that is necessary for compliance.

On the other hand, most companies are complying with the section of the guidance that relates to process qualification. Including a review of in-process testing in their annual product reviews (alongside a review of equipment, the production process, and process changes), many companies also are carrying out the continued process verification that the guidance recommends. Although manufacturers may still have unanswered questions about why three batches are taken for validation?

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