Top Tips for Organic Solvent Cleaning

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In addition to water, other chemical solvents are often added to cleaners to boost performance. i.e. 2-Butoxyethanol (butyl), isopropyl alcohol (rubbing alcohol) and d-Limonene. Their main function is to liquefy grease and oils or dissolve solid soil into very small particles so surfactants can more readily perform their function.

In the traditional approach for cleaning in API industries, same solvent is used for cleaning which is used during the synthesis. As the solubility of this solvent is more for that API compare to other solvent. The most widely used cleaning solvent in the industry i.e. methanol, acetone, dimethyl formamide and ethyl acetate.

Advantages of organic solvent cleaning

  • The API is usually soluble in the organic solvent.
  • The solvent may be readily available and routinely used in the manufacturing process.
  • Solvent residue analysis is simple, and may be unnecessary if the cleaning solvent is the same as the process solvent in the next batch.

Disadvantages of organic solvent cleaning

  • Residues other than the active ingredient i.e degradants, byproduct may be soluble in the cleaning solvent if they are present on the surface.
  • The traditional approach of refluxing is time consuming.
  • As the solvent evaporates the residue also has the potential to redeposit on surfaces
  • Discarding large amount of cleaning solvent can be issue.
  • Solvent can be recovered which add to overall cost of manufacturing.

Builders

Builders are used as an alternative to chelating agent which effectively reduce the cost of the formulating detergent. i.e. Phosphates, Sodium Carbonate
Advantages of builders

  • Added to cleaning compound to upgrade and protect cleaning efficiency of the surfactants.
  • Having number of functions like softening, buffering, and emulsifying.
  • Builders soften water by deactivating hardness minerals (metal ions like calcium and magnesium.
  • Builders also provide a desirable level of alkalinity (increase pH), which aids in cleaning.
  • Builders are also act as buffers to maintain proper alkalinity in wash water.

Typical Cleaning Cycle Description

If the product residue is the buffer or salt which are easily soluble in hot water, the cleaning can be done with only water rinses. The cleaning will be done with pre-determined number of rinses or can be done during the validation.

If the product is biological compound, then the cleaning cycle has to consist of pre wash, alkali, acid and final rinse of WFI. The cleaning cycle will consist of one or more of these steps, not necessarily the sequence mentioned below,

Pre Wash

  • The pre wash can be with hot and cold rinse highly depend on type of residue
  • The pre-wash helps to get rid of some of the material which are more soluble in Purified water or Water for injection i.e. residual sugar, salts
  • If the protein is used, the Pre wash should be given with ambient temperature, as hot temperature will denature the protein and will stick to vessel surface which will become difficult to clean later
  • Can be send to drain directly without recirculation

Alkali Wash

  • The alkali is supplied with feed pump till the set point reaches supply tank
  • Detergent solution can be heated by passing through heat exchanger
  • Recirculated for specified amount of time then to drain
  • Dissolves the residue which are not cleaned by Pre wash

Post Alkali Wash

  • All transfer lines and vessel should be washed with hot WFI or PW
  • To clean the alkali traces after the alkali wash
  • Can be used in recirculation or send to drain directly
  • Temperature is raised with use of heat exchanger supplied with steam.

Acid Wash

  • Useful to remove specific residues which are not cleaned by alkali and WFI rinses i.e. protein residue are more soluble in acid than in alkali
  • The acidic wash can be given with mild heating, as it is observed foam formation at hot temperature during acid washes
  • Can also be used a neutralization after the alkali wash
  • Recirculated for specific amount of period and then send to drain

Final Rinse

  • Final rinse will be given till the final rinse conductivity equivalent to WFI or as per the set point given
  • The temperature can be ambient or at 70-80 ?C, to clean the remaining final traces of acid
  • Final rinse can be once through or drain intermittently

Air Flushing for Storage

  • Air flushing can be used after each wash or after final rinse only
  • Used for removal of trace WFI or PW from cleaned vessel and transfer lines
  • Used to dry the system
  • If possible every cleaning cycle should end with this step, for better cleaning.

Typical Cleaning Cycles for Systems

The cleaning cycles are custom designed as per design and structure of the equipment to be cleaned. All vessels, fermenters, centrifuges can be cleaned with same cleaning cycle.

Fermenter

For cleaning of the fermenters the cleaning cycles involves Pre wash, alkali wash, post alkali wash, acid rinse, final rinse till the set conductivity reaches. Air blow can be given in between stages, every cleaning cycle should ends up with air blow as to dry the fermenter.

Ultrafiltration System

The ultrafiltration system consists of ultrafiltration cassettes, Holding tank and skid. The cleaning of the tank and skid can be done separately, or done altogether as per the cleaning cycle development.
The ultrafiltration cassettes used during process are depyrogenated first with 2-4% of Alkali and then stored in 0.2-0.5% of alkali till the next usage.

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  • S.Vijay kumar

    Your Comment
    The type of left over in API is normally organic in nature and they are generally soluble in organic solvents and washing with builders or alkali wash can result in reaction with API or its intrmediates which will be difficult to clean with organic solvents.

  • S.Vijay kumar

    Your Comment
    The type of left over in API is normally organic in nature and they are generally soluble in organic solvents and washing with builders or alkali wash can result in reaction with API or its intrmediates which will be difficult to clean with organic solvents.

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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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