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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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‘To the Cloud or not to the Cloud, that is the question.’

While it’s certainly a familiar question, with apologies to Hamlet, there is a question that tends to come first: “What is the Cloud in the first place?” Have you seen this on-line graphic lately of a young child who is just looking at you with the caption – ‘There is no cloud…’

Information Workers

The reality for most ‘information workers’ is that as long as your keyboard, mouse and monitor have something to plug into and data displays, all you really need to see is where that ‘something’ plugs into the wall so you can be sure you have a physical connection.

What’s on the other side of the wall – or even if there is strictly speaking no ‘other side’ – is not the users concern. You don’t need to have physical computing resources right next to you as long as the ‘virtual machine’ you are working on is properly provisioned and the latency (or ‘lag/response time’) isn’t large enough to be an issue.

Enterprise

The physical computing resources matter if you are doing a lab analysis with physical samples on instruments or using an automated line to produce product. In the land of data analysis, reporting and document production, the data needs to be available, not present.

From the enterprise perspective however, what is ‘present’ behind the wall is a true concern. Since compliance to regulations means ‘control,’ how the cloud supplies and protects those resources and the information they provide needs to be documented under a defined quality management system. While cloud vendors are glad to quote services and prices, they have not always been forthcoming about how things are done in their building.

Outsourcing

The move to the cloud is a physical move – of your data, applications and possibly compute and platforms – to somewhere else. The somewhere is physical while your usage and controls become logical and virtual. If that makes you feel uneasy – or if you prefer ‘risk averse’ – you are not alone.

Outsourcing is a concept that brings joy to financial / accounting types, but for those involved with compliance, quality and validation, it brings a new set of challenges and concerns. It should recall the words of Mr. Murphy – “Nothing is as easy as it looks, everything takes longer than you expect AND if anything can go wrong, it will – usually at the worst possible time.”

Current warning letters addressing data integrity have focused on site forensics – data in trash cans, bags of shredded records. When it comes to the cloud, there is no ‘there’ for you to access – unless there are the careful negotiations, detailed SLAs and rigorous audit/ follow-up required to give your enterprise the confidence it needs to move forward.

Do your current internal resources have the expertise and the flexibility to deal with a vendor you have to trust significantly? This is more complex than a contract manufacturer where you can review the SOPs for compliance, watch the process and then have the product independently tested.

GxP Compliance

The draw of the cloud is that everything is ‘out there’ – available ‘just by an e-mail’ – and not running up costs on your premises. What will happen if suddenly it isn’t ‘there?’ Whose fault will it be – oh, must be the vendor. Good idea – blame the vendor – but there’s many a wire between your ‘here ‘ and their ‘there.’

Will it be your communication vendor, some nameless third party supplier or cloud hardware, software or internal network failure? There are many ABCs in the cloud – SaaS, IaaS, PaaS, Haas, AaaS, ITaaS – and the list goes on. It is critical to have the proper support to be able to straighten all those letters out to spell ‘GxP compliance.’

Cloud Provider

Everyone wants their cloud provider to look like the image below. But that will take attention to detail, technical understanding and the ability to ask ‘the next questions’ needed to assure quality and compliance.

Those will include security at multiple levels and how are they going to maintain those perfect cables when the one in the middle breaks?

There are many items to be considered – here are some more:

  • What application(s) and data are going to be ‘sent to the cloud?’
  • What in-house processes / systems need to access that data?
  • Where will the data physically be held and what are the laws in that location if outside of the USA?
  • What are the backup provisions for the cloud providers’ servers and storage?
  • What is the security plan – including physical, logical and access controls?
  • How will your audit resources be granted access and under what ground rules?
  • Does the vendor provide a Quality Manual or Quality Management System document for review?
  • Does their contract include a ‘non-cookie cutter’ Service Level Agreement (SLA) that details your focus points?

John English is an independent contractor with The Azzur Group.

If you would like any help with CSV related projects please visit www.azzur.com.

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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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