How to Write an Effective Cleaning Procedure

During early stages of the cleaning method validation or after introduction of the new process equipment or cleaning equipment the egg and hen dilemma (Cleaning SOP first or cleaning validation first) is normally observed.

To start the cleaning method validation, the approved cleaning method (Standard operating procedure for cleaning of the equipment) is required and to write the Standard operating procedure for cleaning (SOP), the validation is required.

Imagine a new drug product manufacturing facility, or new equipment train or introduction of the new process equipment and still not in use. The seeding of the cleaning method shall be done at this stag itself to have the strong pillar for the cleaning method with the aid of the accessories installed on the process equipment for the cleaning (e.g. Spray ball for the tank cleaning) or by using the dedicated equipment required for the cleaning like Cleaning in Place (CIP) unit, or ultrasonic bath for the very small product contact surface accessories.

The right approach to resolve the Hen and Egg dilemma would be, to incorporate the study in the performance qualification protocol of the CIP or Process equipment or the cleaning accessories, The qualification of the cleaning equipment may be performed in two stages. Each stage will be data base for writing the SOP for the cleaning.

Stage: 1: Rinse policy determination :

The First would be using the dummy chemical for batch manufacturing and using the Riboflavin. e.g. use of the sodium chloride or Sucrose or other appropriate chemical having lower detection unit ( We will write the Sodium Chloride in further write up as the representative of these chemicals ).This stage will help to write the approach to the rinse sampling ( Performed during normal production run ) and the use of the riboflavin will have the basis for the swab sampling methodology for writing the SOP for the cleaning of the equipment.

Let us see it stage wise. During first stage of the qualification of the cleaning equipment or process equipment installed with the cleaning accessories, prepare the batch of the sodium chloride or spread the solution of the sodium chloride on the on the product surface of the equipment. Clean the equipment by using the cleaning devices by using measured quantity of the water. Take the rinse sample for the analysis and analyze the sample for the presence of the sodium chloride. Clean till the sodium chloride does not appear in the rinse sample.

That’s it, now we the data base for the quantities of the solvent to be used for the cleaning and the number of the cycles required for the cleaning. This database will help in writing the cleaning method and the rinse sampling for the cleaning method validation.

Stage: 2: Swab Policy determination

Now we are ready to decide the swab sampling, The most important part of the swab sampling is the swab sampling be done on the hard to clean location. Now we have to decide the hard to clean surface. This will be stage 2 of the Performance qualification of the equipment or accessories used for the cleaning.

Overlay the Riboflavin on whole inner surface of the equipment including the crevices and the remote parts and run the first cycle of the cleaning (Decide the cycle parameters of cleaning here itself). With the aid of the UV light observe carefully the whole surface of the equipment after completion of the first cycle (The riboflavin gives fluorescence under UV light). If no fluorescence is observed on any of the product contact locations, Good!

The cleaning accessory or cleaning equipment can clean the equipment overlaid by the riboflavin by using the decided cycle parameters If after completion of the first cycle the riboflavin is observed on the equipment then mark the locations on the drawing or photograph of the equipment where the riboflavin is observed. Run the similar cycles till the riboflavin is completely eliminated and go on marking on the drawing or photograph of the equipment (Modification in the cycle parameters like qty of the solvent used, or the cycle time etc may be done to have effective cleaning, but this will lead to repetition of the entire process of cleaning again, right from the overlaying surface of the equipment with the riboflavin and rinse procedure).

Determine the hard to clean locations by observing the photographs marked for the presence of the Riboflavin. The repeated cycles will determine the hard to clean locations. Normally the remote locations or crevices of the process equipment are hard to clean surfaces. If the determined “Hard to clean surfaces” are surprisingly not obvious surfaces which shall have been observed cleaned, then we may have to modify the cycle parameter.

If specialized equipment like CIP is used we have ample of parameters to modify and if the simple cleaning accessory attached to the process equipment (Like spray ball) is used then we have limited parameters to manage. After varying these parameters I it is concluded that the cleaning can not be performed by this cleaning accessory, the performance of the same is in question and we have to look for the accessory with higher capacity or different design.

Writing the Standard Operating Procedure

After completion of the study, all the study data shall be addressed in the performance qualification report of the equipment. This report will stand as the basis for writing the Standard operating procedure for the cleaning of the equipment. After performing all the above exercise, we have following data in hand.

  • Number of the rinse required to clean the equipment with no detectable sodium chloride and riboflavin.
  • Quantity of the solvent used for each cleaning cycle
  • Hard to clean surfaces for the given process equipment by using the said cleaning accessory.

Now, we are ready to draft the SOP for the cleaning of the equipment.
While writing the SOP for the cleaning, mention the following things in the SOP as determined after the above mentioned study.

  • Write the quantity of the solvent and cycle parameters in the SOP as set during the above study
  • Write the number of cycles in the SOP required for cleaning, the number of cycles shall be the maximum cycles as performed during the rinse analysis (Stage : 1) or swab analysis (Stage :2) in above study. Since we have used the sodium chloride and riboflavin, it may be easier to clean than the planned products. Hence while writing the SOP consider the number of cycles one or two more than performed during the study, this will help to minimize the further revision of the SOP after introduction of the more hard to clean product
  • Mention the hard to clean surface in the SOP, so that swab sampling of the same location will be performed

The Takeaway

Now we will have the good SOP for the cleaning of the equipment with the sound background and we are ready to use the process equipment and cleaning equipment for production purpose. On introduction of the new product we will check the feasibility of the current procedure (Validated on the Sodium chloride and the riboflavin with one or two extra cycles) to clean the product. This will be a continuous process as the products go on adding.


  • snjv.dv

    Sir can u tell me about dirty hold time study

  • snjv.dv

    Sir can u tell me about dirty hold time study

  • Dear Sir / Madam

    Can we use UV torch for checking the cleanliness of equipment routinely?

  • Dear Sir / Madam

    Can we use UV torch for checking the cleanliness of equipment routinely?

  • urmi kantaria

    please tel me about cleaning validation for any equipements using any example of drug and reply me as soon as possible…

    thanking you.

  • urmi kantaria

    please tel me about cleaning validation for any equipements using any example of drug and reply me as soon as possible…

    thanking you.

  • santhosh

    its good.sir can u please provide the information about how much surface area required for swab sampling for different types of equipment

  • santhosh

    its good.sir can u please provide the information about how much surface area required for swab sampling for different types of equipment

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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.


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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