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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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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