Knapp Testing & Manual Inspection – What Do You Think?

A Knapp test is carried out to ensure that the manual inspection is similar to the automated process of inspection. It is a very lengthy process, but this document is generally asked for if you qualify an automated machine for inspection by an auditor.

The Knapp test is as follows:

Firstly, the USP states “all parenterals will be 100% visually inspected.”

Secondly, below are my opinions only (experience) and if I fail to identify anything that a regulator may be looking for, or if someone with more experience can add to anything or correct anything, I will truly value the feedback.

When developing a method in which to qualify operators it is important to develop a process for qualifying that you can easily defend.

The following discussion is something we can call the ‘pseudo Knapp method’

The PDA presents papers on Julius Knapp’s methodology to use when validating a semi-automated inspection method (eg. siedenaders) or fully automated inspection machines (eg. EISAI) so these can be used for reference.

Particulate Rejects

The best thing to do is collect particulate rejects from various batches (keeping the characteristics of the product the same – eg. viscosity, clear or yellowish, fill volume, etc…)

Uninspected Vials

After collecting X numbers of particulates rejects from various batches, these vials can be blindly placed into Y number of uninspected vials from various batches.

Inspectors

Now with X + Y, have inspectors (let’s say three different inspectors) manually inspect these vials 10 times each (3 inspectors times 10, times each vial, is 30 inspections each vial) . Using Knapp’s probabilistic methodology, anything with a probability of 0.7 is classified as a reject.

Thus from the X + Y, any vials that were rejected 21 out of 30 times would be considered a reject. Using these vials classified as rejects and using vials that are classified as good vials (anything with a probability of 0.3 and less) a standard qualification set can be created.

Note: it is best to get reject vials that have a reject probability of 1.0 (30/30) to make things easier in the end.

Probabilistic Model

Let’s say for example we create a set of 100 vials with 30 vials being rejects, and 70 being good vials classified per Knapp’s probabilistic model.

Other terms that need to be defined include:

RZE – Reject Zone efficiency = sum of reject probability of the 30 reject vials / 30 reject vials
RAG – Reject Accept/Grey = sum of probability of rejecting the 70 Accept and Grey vials / 70 vials

NOTE: I did not discuss grey vials, don’t see a need but this can be incorporated

Probabilities of Rejection

Now we should determine the RZE of the set. Adding up the probabilities of rejection from the 30 reject vials, (eg. let’s say its 28) Thus the RZE = 28/30 = 0.93. J. Knapp states that an RZE of 0.80 and 0.95 is what is normally seen in industry, so determine an RZE that suits your business, also your business would also want a low RAG (RAG should be less than 0.10, but is also based on what you sets RAG is) which is considered how your operators will react to good product.

Now you can test your operators using this set and calculate the RZE and RAG values to identify operators for inspection.

Conclusion

After writing this, I know that there are many things that have been left out, for example, you need to verify the visual accuracy of your inspectors (eye test done during hiring). In addition, your product set may degrade over time causing it to form particulates so you may need to store the set at the product requirements to impede degradation, or replace the set on an on-going basis.
I would be most grateful for any other comments on this subject.

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  • mmbabaee

    I want to know for manual inspction for knapp test, can we use magnification? or we can compare the machine with normal human optical capability .

  • pkelly

    Is performing a Knapp Test necessary for validation of a manual inspection protocol? What is best/standard practice for validation of a manual inspection protocol?

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An Alternative View of the ICH Q10 Pharmaceutical Quality System (PQS)

The image below is that depicted by the International Conference of Harmonisation (ICH) Q10, Annex 2, and is supposed to depict a PQS or Pharmaceutical Quality System.

Typically, I really love the ICH. When we have to deal with outdated regulations from different global organizations it becomes a real nightmare trying to keep track of the nuances and the ICH has done a pretty good job of bringing several of the key organizations together and aligning them on how best to organize and meet the expected requirements.

That being said the diagram below and the depiction in Q10 of what a PQS should look like is greatly lacking.

Development Phases

In section 1.8 under the Quality Manual the ICH Q10 guidance states, “The description of the PQS should include: …(c) Identification of the pharmaceutical quality system processes, as well as their sequences, linkages and interdependencies.

Process maps and flow charts can be useful tools to facilitate depicting the pharmaceutical quality system processes in a visual manner”.

I completely agree.

The problem is using the graphical depiction they present in Annex 2 is completely worthless.

Basically they listed some of the PQS elements in a bar and then said they all apply to the entire product lifecycle, which simply isn’t true.

When we are in the development phase of our product lifecycle why would we do that under the change management system, or monitor process performance?

 

Controlling Change – No Value Add

There is no point in controlling changes for a product that is purposely being changed, nor does it offer any value to monitor the process performance for a process that has yet to be developed.

This isn’t a graphic depiction of the PQS, but rather a graphic of how they depict the lifecycle management (which also has some issues).

The PQS is the quality system and its subsystems and how they interrelate.

While it’s useful to look at how the PQS and product Lifecycle Management overlap and what elements of the PQS system are relevant at each lifecycle stage, it is not the point of the PQS, and even if that’s the end goal it’s not depicted here at all.

This image offers almost no value.

A Better Approach

So, what should this graphic look like?

While this is not a perfect view of a PQS, I would propose that the image below is a much better depiction of how the PQS should be visualized and a good place to start.

At the core of any quality system should be management. This goes back to Deming, who said, “Quality begins with the intent that is fixed by Management”.

Quality has to be rooted in the executive management team.

Define Core Quality Systems

Core quality systems then need to be defined. These are systems that impact all aspects of the business and include a Risk Management Policy, Resource Management, Document Control and CAPA systems.

All of the other subsystems, Deviations, Supplier Management, Equipment Qualifications, Validation, Material Management, etc, etc. all should be risk based or involve risk assessment, they all require resources and training, they call require documents (procedures, policies, records), and the CAPA system of course drives for process improvement regardless of the process.

Subsystems

All subsystems feed back into the main Management module. The subsystems listed, all are interconnected, with the exception of Post Market Systems.

The subsystems are important too, but they are farmed out to different groups and have different levels of importance depending on the stage of the product lifecycle.

Post Market Systems

The one exception is the Post Market Systems. This includes complaint management, product reviews, recall processes and other systems to support marketed products.

These generally do not interact with the other subsystems unless it is through the CAPA system or other management functions, but still utilizes all the systems under the management umbrella.

Alternate View

The PQS presented here, isn’t intended to be perfect, but I thought it was worth presenting an alternate view to the one presented by the ICH.

The ICH concept is a good one, and the ideas are fairly well laid out in the ICH, but the graphical representation of the PQS leaves a lot to be desired.

When establishing a PQS, it is better to start with something to what we’ve depicted here, and customize it as needed for the organization.

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How 21 CFR Part 11.3(7) Applies to Electronic Batch Records [Video]

When dealing with Part 11 it’s important to understand what an electronic signature actually means

The definition of electronic signatures or e-sigs can be found in 21 CFR Part 11.3(7).

Electronic Signature

An electronic signature or e-sig means a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.

Handwritten Signatures

We also need to understand what a handwritten signature means in the context of Part 11.
The definition of handwritten signatures can be found in 21 CFR Part 11.3(8).

Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form.

The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.

Electronic Batch Records

Eric works in a Pharmaceutical company and he is responsible for the filling process of the batch been manufactured.

Each time Eric performs the filling process he has to populate a batch record with the appropriate details

After each step Eric must also fill in his signature and date to verify that he actually performed each task.

Eric is manually handwriting these details and they are legally binding to Eric.

21 CFR Part 11.3(8)

This is when 21 CFR Part 11.3(8) applies.

Fast forward 12 months and Eric’s company has implemented a brand new Manufacturing Execution System (MES) where all details around the batch manufacturing process are recorded electronically.

21 CFR Part 11.3(7)

Now when Eric performs the filling process he now populates everything electronically and signs with his username and password combination to verify that he has performed those tasks.

This is when 21 CFR Part 11.3 (7) applies.

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