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

  • http://www.cipla.com D G Rudrawar

    Dear Sir / Madam

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

  • http://www.cipla.com D G Rudrawar

    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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Changes to equipment and documentation is an integral part of the whole GMP process in any regulated facility. In this article we will discuss how equipment is designed in a GMP facility and how good documentation practices are an essential part of quality assurance and GMP.

The content of this article has been taken from module 7 of our eLearning module on Good Manufacturing Practices (cGMP) within the life sciences.

You can view this module in full by viewing the video below.

cGMP eLearning Module – Compelling, Engaging and Interactive

 

Equipment

All equipment is designed, constructed and located to suit their intended use and to facilitate easy maintenance and cleaning.

Equipment is installed in such a way as to prevent any risk of error or of contamination, and cleaned according to detailed and written procedures and stored only in a clean and dry condition.

Production equipment should be designed in such a way as not to present any hazard to the products.

The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

Any defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective. When not in use, equipment should be covered to ensure it remains clean.

Balances

Balances and measuring equipment of an appropriate range and precision should be available for production and quality control operations.

All measuring devices are required to be calibrated and checked at defined intervals by appropriate methods, and adequate records of such tests should be maintained.

Utilities

Fixed piping should be clearly labelled to indicate the contents and where applicable, the direction of flow.

Water pipes used in production (e.g. Purified Water, Water for Injection) are sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

Electrical circuits should be identified, and a record maintained of the load on each circuit to prevent inadvertent overload.

Documentation

Good Documentation Practices are an essential part of quality assurance and GMP.

It is important for a manufacturer to get the documentation right in order to get the product right.

GMP Documentation e.g. Site Master File, Specifications, Batch Manufacturing Formulae, Batch Manufacturing Records, Processing, Labelling, Packaging, Testing Instructions, Standard Operating Procedures, Protocols, Technical Agreements, Records, Certificates of Analysis, Reports etc. should contain the following attributes of a good document:

They should be:

  • Attributable
  • Legible
  • Contemporaneous
  • Original
  • Accurate
  • Complete
  • Durable
  • Corroborated
  • Version Based
  • Accessible
  • And Authorized

Change Control

Change to GMP documentation, equipment, processes, systems, instrumentation, test methods, etc. are required to be controlled under a formal change control program.

This program must consist of Quality oversight to review the proposed changes, evaluate the potential impact of the change, determine any potential risk to product quality, and to establish the required level of supplemental validation/documentation required for the change.

In many instances, changes will also require submission to the Health Authority for approval of the change.

For example, changes impacting the submission documentation are subject to post approval change guidances according to the Health Authority regulations.

Change Control is a critical aspect of the GMP systems.

If you want to learn more about cGMP or if you want to evaluate our eLearning module for your company you can find more information here.

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The enduring assets of a laboratory’s work are the records that document those activities. When laboratory records are used to support a regulatory function, they are considered to be legal documents.

Laboratory Data Integrity – eLearning Course

 

For records to be considered reliable and trustworthy they must comply with the following criteria:

  • Legible and Understandable – they must be able to be read and understood for the lifetime of the record, without having to refer to the originator for clarification. The information may be needed in five, ten or twenty years’ time, perhaps after the originator is no longer available
  • Attributable – who made the record or created the data and when?
  • Contemporaneous – the record must be made at the time the activity was performed
  • Original – the information must not be written on a post-it, piece of scrap paper, sleeve of a lab coat etc. and then transcribed.
  • Accurate – no errors or editing without documented amendments
  • Complete – All the information and data associated with the analysis is included
  • Consistent – All elements in the sequence of analysis must be date & time stamped and must be in the expected order
  • Indelible – Records are made on to controlled documents, such as laboratory notebooks or controlled worksheets, or saved to electronic media
  • Available – over the entire lifetime of the record for review, audit and inspection

1. Legible and Understandable

A record that cannot be read or understood has no value and might as well not exist. All records should be composed so they conform to grammatical convention which should be consistent throughout.

It is best to avoid buzzwords, cliques and slang as these are prone to change with time and are often not understood outside a particular locality. It is always good practice to have any record reviewed by a second person as this can often highlight any ambiguities.

2. Attributable

The identity of the person creating a record should be documented. For paper records this is normally done by the individual signing and dating the record with their signature.

As the record you may be signing may be a legal document, you should clearly understand the implication of your signature. A signature should be individual to a specific individual and the practice of signing someone else’s name or initials is fraud, and is taken very seriously.

3. Contemporaneous

All records must be made at the time an activity takes place. Delaying writing up, for example until the end of the day, will inevitably affect the accuracy of that record as details can be forgotten or miss-remembered.

4. Original

All records must be original; information must be recorded directly onto the document. This avoids the potential of introducing errors in transcribing information between documents.

If information from an instrument is printed out, by the instrument, that printout is the original record and should be signed, dated and attached to the record.

5. Accurate

The record must reflect what actually happened. Any changes should be made without obscuring or obliterating the original information, the use of whiteout or correction fluid is prohibited.

Any changes made to a record should be signed by the person making the change and dated to show when it was made and a written explanation should also be provided. Remember, the record may be needed after you have left the company and cannot be contacted for clarification.

6. Complete

The record must contain all information associated with the analysis of the sample, including system suitability tests, injection sequences, processing methods, sample preparation procedures and results.
This must also include any reinjections or repeat analysis performed on the sample.

Remember the position of the regulatory authorities for something that needs to be done is – ‘if it isn’t documented it’s a rumour’. However, failing to disclose reanalysis or reinjection of samples will undermine confidence in the reliability of the records.

7. Consistent

Consistency in this context refers to the sequence of the component events, which the analytical method comprises, being performed in a logical order.

For example it is not possible to commence the HPLC run before the samples have been prepared, therefore the balance printout for the sample weights should be date/time stamped at least one or two hours prior to the sample injection time, to allow time to prepare the samples. Therefore all date/time stamps should be in the expected sequence.

In order to avoid confusion in this respect, it is worth ensuring all instruments that produce date/time stamped printouts are time synchronised. This is best done by reference to a standard reference time, such as a national online time server.

8. Indelible

Indelible means the record must be legible for the lifetime of the record and once it has been made it cannot be removed.

Hand written entries of information should be made in ink and not pencil which can be erased

If printouts are made on thermal paper, which darkens with time, a photocopy should be made; this should be certified as an accurate copy of the original print and attached

If print outs are attached to a page they should be

  • Secured to the page with acid free glue and industrial strength Sellotape
  • Signed and dated across the attachment and the page
  • Annotated with a reference to the document

9. Available

All records should be available for inspection, audit and review for the lifetime of the document. If a document is requested during a regulatory audit, it should be produced within thirty minutes.

Therefore, the laboratory should establish an easy to reference archive system. Records should be archived so as to preserve their integrity, such as

  • Secure facility with restricted access
  • Effective fire suppression
  • Protection from dampness or humidity
  • Controlled access to Document

Check Out Our Laboratory Data Integrity eLearning Module

If you are looking for a way to train your staff on the importance of data integrity in a regulated environment check out oureLearning Course.

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