Why Do We Have Out of Specifications (OOS) and Out of Trend (OOS) Batches

    Amrendra Roy


    While developing a product, we are bound by the USP/EP/JP monographs for product’s critical quality attributes (CQAs) or by the ICH guidelines and we have seen regular OOT/OOS in commercial batches. It’s fine that, every generic company have developed an expertise in investigating and providing corrective & preventive action (CAPA) for all OOT and OOS, but question that remained in our heart and mind is that,

    Why can’t we stop them from occurring? 

    Answers lies in following inherent issues at each level of product life cycle,

    We assume customer’s specification and process control limits are same thing during the product development.

    Let’s assume that USP monograph gives a acceptable assay range of a drug product between 97% to 102%. The product development team immediately start working on the process to meet this specifications. The focus is entirely on developing a process to give a drug product within this range. But we forget that even a 6sigma process has a failure rate of 3.4ppm. Therefore in absence of statistical knowledge, we consider customer’s specification as the target for the product development.

    The right approach would be to calculate the required process control limits so that a given proportion of the batches (say 95% or 99%) should be in between customer’s specifications.

    Here, I would like to draw an analogy where the customer’s specification like the width of a garage and the process control limits is like the width of the car. The width of the car should be much less than the width of the garage to avoid any scratches. Hence the target process control limits should be narrower for the product development.

    For detail see earlier blog on car parking and 6sigma“.

    Inadequate statistical knowledge leads to wrong target range  for a given quality parameters during Product development.

    Take the above example once again, customer’s specification limit for the assay is 97% to 102% (= garage width) now, the question is, what should be the width of the process (= car’s width) that we need to target during the product development to reduce number of failures during commercialization? But one thing is clear at this point, we can’t take customer’s specification as a target for the product development.

    Calculating the target range for the development team

    In order to simplify it, I will take the formula for Cp


    Where, Cp = process capability, σ = standard deviation of the process, USL & LSL are the upper and lower specification of the customer. The number 1.33 is least desired Cp for a capable process = 3.9 sigma process.

    Calculating for σ


    Calculating the σ for the above process


    Centre of the specification = 99.5 hence the target range of the assay for the product development team is given by

    Specification mean ± 3σ

      = 99.5±3×σ = 99.5±1.89 = 97.61 to 101.39

    Hence, product development team has to target an assay range of 97.61 to 101.39 instead of targeting the customers specifications.

    There is other side of the coin, whatever range we take as a target for development, there is a assumption that 100% of the population would be in between that interval. This is not true because, even a 6 sigma process has a failure rate of 3.4 ppm. So the point I want to make here is that we should also provide a expected failure rate corresponding to the interval that we have chosen to work with.  


    For further discussion on this topic, keep vising for the forth coming article on Confidence, prediction and Tolerance intervals

    Not Giving Due Respect to the Quality by Design Principle and PAT tools

    Companies not having in-house QbD capability can have an excuse but even the companies with QbD capability witness failures during scale-up even though they claim to have used QbD principle. They often think that QbD and DoE are the same thing. For the readers I want to highlight that DoE just a small portion of QbD. There is a sequence of events that constitute QbD and DoE is just on of those events.

    I have seen that people will start DoE directly on the process, scientist used to come to me that these are the critical process parameter (CPPs) and ask for DoE plan. These CPPs are selected mostly based on the chemistry knowledge like, moles, temperature, concentration, reaction time etc. Now thing is that, these variables will seldom vary in the plant because warehouse won’t issue you less or more quantity of the raw material and solvents, temperature won’t deviate that much. What we miss is the process related variables like heating and cooling gradient, hold up time of the reaction mass at a particular temperature, work-up time in plant (usually much higher than lab workup time, type of agitator, exothermicity,  waiting time for the analysis and other unit operations. We don’t understand the importance of these at the lab level, but these monsters raises their head during commercialization.

    Therefore a proper guidelines is required for conducting a successful QbD studies in the lab (see the forth coming article on DoE). In general if we want a successful QbD then we need to make a dummy batch manufacturing record of the process in the lab and then perform the risk analysis to the whole process for identifying CPPs and CMAs. Brief QbD process is described below


    Improper Control Strategy in the Developmental Report

    Once the product is developed in the lab, there are some critical process parameters (CPPs) that can affect the CQAs. These CPPs are seldom deliberated in detail by the cross functional team to mitigate the risk by providing adequate manual and engineering control. This is because we are in a hurry to file ANDA/DMF and other reasons. Once the failures become the chronic issue, we take actions. Because of this CPPs vary in the plant resulting n OOS.

    Monitoring of CQAs instead of CPPs during commercialization.

    I like to call ourselves “knowledgeable sinners”. This because we know that a CQA is affected by the CPPs even then we continue to monitor the CQA instead of CPPs. This is because, if CPPs is under control, then CQA will have to be under control. For example, we know that if reaction temperature shoots, it will lead to impurities, even then we continue to monitor the impurities level using control charts but not the temperature itself. We can ask ourselves what we can achieve by monitoring the impurities after the batch is complete? Answer is we achieve nothing but a failed batch, investigation, loss of raw material/energy/manpower/production time, to summarize we can only do a postmortem of a failed batch and nothing else.

    Instead of impurity, if we have monitored the temperature which was critical, we could have taken an corrective action then and there itself. Knowing that this batch is going to fail, we could have terminated the batch thereby saving loss of manpower/energy/production time etc. (imagine a single OOS investigation required at least 5-6 people working for a week, which is equal to 30 man days.


    Role of QA is mistaken for Policing and auditing rather than in continuous improvement.

    The QA department in all organization is frequently busy with audit preparation! Their main role has got restricted to documentation and keep the facility ready for audits (mostly in the pharmaceutical field). What I feel is that, within the QA there has to be a statistical process control (SPC) group, whose main function is to monitor the processes and suggest the areas of improvements.  This function should have sound knowledge of engineering and SPC so that they can foresee the OOT and OOS by monitoring CPPs on the control charts. So, role of QA is not only policing but also assisting other departments in improving quality. I understand that at present SPC knowledge is very limited among QA and other department, which we need to improve.

    Lack of empowerment to the operators for reporting deviation occurred

    You all will agree, the best process owner of any product is the shop-floor peoples or the operators but, we seldom give importance to their contribution. The pressure on them is to deliver a given number of batches per month to meet the sales target. Due to this production target, they often don’t report deviations in CPPs because they know if they do it, it will lead to investigation by QA and the batch will be only cleared once the investigation is over. In my opinion, QA should empower operators to report deviations, the punishment should not be there for the batch failure but for not asking for the help. It is fine to miss the target by one or two batch but the knowledge gained from those batches with deviation would improve the process.

    Lack of basic statistical knowledge across the technical team (R&D, Production, QA, QC)

    I am saying that everyone should become an statistical expert, but at least we can train our people on basic 7QC tools! that is not a rocket science. This will help everyone to monitor and understand the process, shop-floor people can themselves use these tools (or QA  can empower them after training and certification) to plot histogram, control charts etc.. pertaining to the process and can compile the report for QA.

    What are Seven QC Tools & How to Remember them?

    Other reasons for OOT/OOS are as follows which are self explanatory
    1. Frequent vendor change (quality comes for a price). Someone has to bear the cost of poor quality.
      1. Not linking vendors in your continuous improvement journey. The variation in his raw material can create a havoc in your process.
    2. Focusing on delivery at the cost of preventive maintenance of the hardware’s

     Related Topics

    Proposal for Six Sigma Way of Investigating OOT & OOS in Pharmaceutical Products-1

    Proposal for Six Sigma Way of Investigating OOT & OOS in Pharmaceutical Products-2



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    6 thoughts on “Why Do We Have Out of Specifications (OOS) and Out of Trend (OOS) Batches”

    1. Its true Dr.roy. QA is not only to show the traffic light and they can assist in terms of how to reduce the defect occurrence through CPV effectiveness. l strongly beleive that preventive measure & control strategy can protect the defect waves.

      The way you presented its realy impressed. Keep doing good…all the best.

    2. It is very true. Based on this at least we can improve our ability and resources to get better product quality with minimum failures.

      1. Thanks for the reply, I am in the process of making a draft guidelines for the same.
        Have a look at other articles and keep commenting and suggesting for improvement

    3. It’s true but main theme of pharma industries are to give faster dispatch and filing of ANDA.Investigation of OOS and OOT during commercial batches takes lot of time to finish so we have to be optimistic during process development CPP.Hopes to be there soon!

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