Monthly Archives: April 2022

The Boiling Frog Syndrome in your Pharmaceutical Stainless Steel Hot Systems?

Rouge is the type of corrosion that occurs in Stainless Steel, especially in Stainless Steel hot systems is akin to Cancer in human beings or can be related to the ‘Boiling frog syndrome. On most occasions, it is ignored with serious ramifications. Periodic check-ups facilitate early & level of severity detection. Ignore it and the rouge worsens leading to many challenges damaging the surface finish, severe corrosion eventually has the potential to affect the product quality in Pharmaceutical Stainless Steel Hot Systems.

These days when leading pharmaceutical companies are spending millions to build a manufacturing facility which does not add any contamination to the drug, the danger of rouge and its effect on the contamination of medicines are most times overlooked. There are many examples wherein companies had to scrap part or full systems handling WFI, Pure Steam, etc. due to severe rouge. The reasons for discard were either visual inappropriateness or its effect on the product in contact. The innocuous thin black or red slimy or powdery deposit gradually worsens and spreads like cancer from high-temperature zones to low-temperature zones as well. Essentially, "rouge" is composed of corrosion products of hydrogen and iron oxides in different states of oxidation. The colour range is varied due to the various oxides of ferric ion and the corrosion products of hydrogen. The exact explanation for the rouging phenomenon is not yet clearly understood, but it is possibly the outcome of momentary destabilization within the passive surface.

See the visuals shown –

There are means to avoid or delay rouging altogether –

  • Right selection of SS
  • Electropolishing (and hence suppressing the Iron exposure)
  • Avoid any iron source that can contaminate Stainless Steel

And then there is Praj Hipurity which can help you eliminate or reduce the incidence of Rouging post facto. Praj HiPurity system Ltd. has helped many organisations treat their rouging problems whether it is Type 1, Type 2 or Type 3. Depending on the type of equipment or systems, different processes like chemical derouging or electropolishing can be employed.

Avoid the ‘Boiling Frog Syndrome’ and contact for your derouging needs.

From Speed to Timing! Way forward in Parenteral Facilities design.

“Speed is irrelevant if you are going in the wrong direction” -Mahatma Gandhi

For parenteral products, sterility is a key product attribute for product safety. The key words in Advances and challenges in Sterile Formulation, Manufacturing and Regulatory aspects show –

  • Drug Safety
  • Endotoxins
  • Process Controls
  • Safe Use
  • Sterilization

A key word we forget here is RFT (Right First Time) facility design EARLY in the project, capable of delivering all of the above. As we fondly tell all our industry friends in Sterile Pharma - Sterility starts from the outlet of WFI system and has to be sustained till the drug is dispensed in a filling machine. The WFI produced in WFI generator –

Unless - not stored and distributed well,

Unless – not dispensed in sterile & efficient manner to the Process skids,

Unless – not formulated in process skids appropriately,

Unless – not seamlessly transferred to filling machines

Most projects of the past assumed great speed while ordering Water systems, Process Skids, Filling Machines, TCU’s etc. The key elements of design which are important and often overlooked are the integration/ handshake between each of these systems. Many times they come as an afterthought or incorporated in design much later with initial assumptions that these integration can be managed at later stages of projects. The advantage of speed & momentum achieved earlier quickly is lost out either during detailed engineering & post ordering of these equipment OR worse after the equipment have arrived at site. The last mile connect as they say, usually takes the longest to cover and invariably becomes the show stopper!

Solution – Shifting focus from Speed to Timing

The integration of Clean utilities with Process Skids have to be anticipated and built in design before orders are released (for Water systems, Process Skids, Filling Machines, TCU’s etc.) with clear mechanical, process, software & validation boundaries as well as handshakes well defined. Many Ampoule, Vial, PFS filling machines are difficult to re-design integrate post-supply. This way of pre-empting the integration challenges and incorporating early in design may take time, the ordering may take time; however saves precious amount of time and cost at CQV stages of the project. We at Praj Hipurity are trying to ingrain this in our way of life based on our various experiences with different clients, suppliers, etc.

Lastly, the need of speed is somewhere else. Nothing is as fast as TRUST.

You can trust Team Praj Hipurity to help you with the right integration & handshake designs early in the Project phase either Pre-order or Post-order engineering.

Strategic & coherent approach to process engineering…!!

Entering a Super market without first considering what you want to buy can prove costly, as people tend to buy more than they need. Similarly when discussing the purchase of customised equipment, lack of specific knowledge and a systematic approach may lead to over spending.

I'll touch on a few aspects that need to be thoroughly discussed and the pros and cons weighed before making a decision.

Closed vs Open design: The pharmaceutical industry seeks to move to fully integrated closed processing in continuous mode of operation. The goal is to remove aseptic manipulation that can cause cross- contamination, boost process efficiency, and ultimately, improve patient safety. The open design with aseptic connectors, on the other hand, gives the same level of assurance while also providing better flexibility, reduced capital expenditure, operator friendliness, etc.

Multiport valves selection: Cleanliness and drainability are two of the most important aspects of equipment design. As a result, it must be considered when designing, along with keeping dead legs to a minimum. Multiport valves provide greater flexibility, compact design and reduce dead legs. It can be used in critical areas where there is a higher risk of contamination that could compromise the product profile, such as transfer-in and transfer-out product lines when more than two valves are required. This is to ensure that rigid pipe has the least amount of dead leg as possible and other less critical locations can be achieved by installing 2 way / T-pattern valves with the appropriate slope and angle.

Optimum utility sizing: CIP and SIP are the two most important sequences in terms of water, steam, and energy consumption. Unfortunately, in most cases, it is overlooked, resulting in oversized / undersized utilities. Establishing the capacity need for clean utilities require knowledge of prospective utility usage, analysis to establish which equipment is likely to need utility at the same time and do calculation accordingly. Estimating the utility requirements for standalone equipment is generally easier, but simultaneous judgement is not!!

As long as a logical and systematic method is followed, the operator will have a sufficient utility system to ensure smooth and reliable operation.

Lastly, you can trust Team Praj Hipurity to assist you in making the best choices and designs for each of the aforementioned aspects while adhering to global quality and safety standards.

Riboflavin/Wetting Trial for PW/WFI Tanks – Meeting Protocol Expectations Vs Practicality

Typically almost every alternate interaction with our client friends on clean utilities tankages (Purified Water / Water for Injection) design, usually touches upon spray ball coverage test. Users want to have the spray ball coverage test also called as Riboflavin Test or Wetting Trial mainly because

  • User’s knowledge of CIP for process vessels spilling over to PW /WFI Tank designs
  • Either because it is a query raised by auditors’ in past or

So do PW /WFI Tank really need to undergo Riboflavin / Wetting Trail for clean-ability?

  • PW /WFI Tanks never see product change in their lifetime unlike process vessels
  • PW/WFI tanks don’t see anything but highly purified water with very low conductivity
  • Some PW/WFI Tanks are also designed to undergo SIP at 121 0 C by Pure Steam
  • WFI Tanks are on most occasions maintained at >80 0 C which makes it self-sanitizing
  • Majority of PW Tanks are hot water sanitized at >80 0C on a monthly to quarterly basis

So one can say – PW/WFI tanks are never seeing product change, higher contamination/ impurities and are sanitized intermittently. Do we still need the tanks tested for spray ball coverage test?

Question Remains - Inspite of above points, one can still argue that the top dish still needs wetting to avoid dry patches.

In order to make the tank compliant with wettability/Riboflavin – from design standpoint following process is followed –

In order to meet the minimum flow rate and pressure requirements following challenges are faced –

  • Return Line Flow of PW/WFI loop – the return line flow of PW/WFI is generally set at minimum return line velocity making the return line flow fixed.
    The Challenge: Irrespective of tank size chosen, return line flow always remains pegged at velocity equivalent. The no of spray balls may vary depending on the Tank size.
  • Return Line Pressure : Back Pressure Regulating Valve (most commonly used in the return line) in effect reduces the pressure at spray ball to < 1 bar more often.
    Challenge: Typical spray balls operate in the range upwards of 2 bar.

Though having tank design compliant with wettability /Riboflavin test is desirable, practically during normal operation of PW/WFI loop, the return line flow rate + return line pressure puts limitations on effectiveness of spray ball.

So should the Riboflavin/Wettability Test Requirement be eliminated for PW/WFI Tanks?

Get in touch with Praj Hipurity for the rightful answer!

Micro-organisms in Macro-reactors! Fermentors for all applications

“You’ve got to start with the customer experience and work back towards the technology – not the other way around.” – Steve Jobs

Fermentation is a complex and iterative process with many interdependent parts. One is concerned with not just an organism and its genetics, but also how the physiology of that organism interacts with the fermentation process one is developing. Beyond the biological challenges of developing a process, one has to consider the financial constraints of making a process and company profitable by accessing fermentor capacity, increasing titre, decreasing costs and controlling scale-up risks. This also involves risk analysis with respect to:

  • Market
  • Product
  • Processes
  • Technology

Based on these four factors, scale of fermentors varies widely from 10 L to 3,50,000 L spreading across various applications like Biosimilars, Biotherapeutics, Vaccines, Enzymes, Nutraceuticals, API & Antibiotics. Interestingly, features for all fermentors remain same:

A key word we forget here is RFT (Right First Time) facility design EARLY in the project, capable of delivering all of the above. We are learning to tell all our industry friends in Biopharma – Independent of your product & scale, the key features are NOT negotiable, as your market comprises of living beings. All volumes of fermentor have different set of challenges in their design, construction, testing and validation. Few well-known challenges are:

  • Space constraint in plant: At times high capacity fermentors are built and tested at site.
  • Jacket coverage, jacket type & cooling coil for temperature control
  • Uniform heat transfer for assured sterilization
  • Adequate mass transfer for yield
  • Containment : end-to-end
  • Cleaning validation
  • Recipe-based automatic operation
  • Event log & data security

In addition to this, fermentation experts feel comfortable, if they are able to automate the ‘Pre’ & ‘Post’ of fermentation seamlessly. This includes integrating distribution of CIP, WFI, Purified water, Clean Steam & media before fermentation and integrating to harvest tank, microfiltration & centrifuge after fermentation.

Solution – Shifting from Product to Market & using the Right scale of fermentor

As your market comprises of patients, so complying with product quality and regulatory standards are of paramount importance. Your product is an outcome of process that is developed. This process can be built, tested & validated using technology from Praj HiPurity.  Based on your product and scale, Praj HiPurity can offer fermentors from 10 L to 3,50,000 L.

Integration of utilities, upstream & downstream equipments with fermentors have to be anticipated and built in design before orders are released , with clear mechanical, process, software & validation boundaries, as well as handshakes well defined. This way of pre-empting the needs and then incorporating them early in design, helps to achieve:

  • Safety
  • Seam-less operation
  • Sterility & Containment
  • Consistent yield
  • Data Integrity
  • Validation

We at Praj HiPurity have tried to ingrain this in our way of life, based on our varied experiences with clients, suppliers and consultants.

Nothing is as fast as TRUST. You can trust Team Praj HiPurity to assist you with right solution early in design phase either Pre-order or Post-order engineering.

The V-FACT Lens for sustainable & effective CIP Solutions

“We can’t solve problems by using the same kind of thinking we used when we created them.” –Albert Einstein

High quality drug manufacturing essentially requires effective CIP (Cleaning In Place) and its validation of manufacturing equipment product contact parts. Reliable, Repeatable and most importantly a Cost effective CIP cycle at the end of each production batch is a challenge.

Cost of generating clean utility and treating CIP effluent is a major area of concern for all manufacturing facilities during operation. Because CIP is one of the major areas for clean utility consumption, it calls for an innovative and customized strategy with a predefined recipe to ensure repeatability. There is a general trend in the industry to go ahead with CIP solution preparation considering 1/3rd volume of the subjected equipment (tank) and associated transfer piping during design conceiving stage, same is then continued during CIP validation and continued during plant operations. This generalization keeping the science at bay has high impact on opex and environment!!!

Solution:- Have a granular look at factors defining CIP using the V– FACT Lens 

Volume– Volume of clean utility and chemical required in each cleaning step considering grouping of subjected equipment and piping circuit.

Flow- Flow to ensure turbulence and impact. Selection of appropriate spray device and    pumping system.

Action – Action time of each cleaning step like pre-rinse, wash time and final rinse time. Dirty hold time before starting action is a critical parameter.

Concentration– Concentrations of chemicals considering product specific properties and human/equipment safety.

Temperature– CIP solution temperature considering impact on solubility.

An innovative look on ”V” is critical while defining CIP philosophy which has to be customized for each application differently. Options which can be explored includes

  • Tank less Mobile CIP Skid’s
  • Hybrid Central+Local CIP skid
  • Centralized CIP skid
  • Central CIP skid with multi tank options

ROI on a CIP system lies in RFT (Right First Time) of ”V” selection. Think about what the best CIP system design is for your process goals and where the system will be located. It is important to define a unique CIP philosophy for each manufacturing line at the beginning of the project.

We at PHS help solve this puzzle using this V– FACT lens for various product applications.