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.

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  • 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

    sir
    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

    sir
    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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The Difference Between Prospective, Concurrent and Retrospective Validation

Unless you’re starting a new company you will need to plan on a variety of approaches.

Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.

In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.

1. Prospective Validation

Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.

This is the preferred approach.

Production is not started until all validation activities are completed.

The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.

The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.

After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.

Periodic Basis

On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.

If any gaps are identified a remediation plan will be developed and the process will start again.

The MVP

The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.

The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.

Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.

2. Concurrent Validation

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.

Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.

The Right Decision?

The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.

As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.

The Process

The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.

Again, routine preventative maintenance, requalification and periodic review are performed.

3. Retrospective Validation

Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.

Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.

Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.

It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.

Historical Data

Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.

During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.

As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.

General Process

The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.

Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.

The MVP should also provide guidance on managing inventory during retrospective validation.

One Major Issue

One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?

As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.

Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.

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International Conference on Harmonization (ICH) in a Nutshell [Video]

The ICH is a common project of regulatory authorities and representatives of pharmaceutical industries in EU, Japan and the US.

Its mission is to discuss issues related to approval and marketing authorization of new medicinal products in these three regions.

Namely, the six parties involved are the:

  • European Commission
  • The European Federation of Pharmaceutical Industry Associations
  • The Japanese Ministry of Health and Welfare
  • The Japanese Pharmaceutical Manufacturers Association
  • The US FDA
  • The US Pharmaceutical Manufacturers Association

In addition to these principals, there are three observers representing non-ICH countries:

  • World Health Organisation (WHO)
  • The European Free Trade Association (EFTA)
  • Health Canada

Primary Objective

The primary objective of ICH is to harmonize regulatory requirements related to quality, safety and efficacy of medicinal products and to support mutual recognitions between the three regulatory authorities.

Exchange of Data

Mutual recognitions are based on the exchange of data and assessment reports which are intended to eliminate duplicative testing and inspection procedures, and thus decrease costs of, and speed up, the introduction of new medicinal products to the markets.

cGMP – Cases from History and the Regulations

If you would like to learn more about the regulations governing the GMP’s click here.

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