Lyophilization
Author: Mr. Amol P. Mane E-mail: amolmane498@gmail.com
Having overall six years of professional experience in the sterile and non-sterile dosage forms of pharmaceutical manufacturing.
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ABSTRACTS :
The main purpose of this article is to clear the basic concepts and principles of the lyophilization process in pharmaceuticals. The successful working of the lyophilizer is dependent upon the scalability, process modeling by using statistical models, and finally trial and error model.
Nowadays trial and error model is very popular. The critical process parameters and critical quality attributes play an important role in the process. The statistical method to be incorporated for the cycle development in which the heat and mass transfer are directly involved in the lyophilization process. Different stages to be monitored as critical such as the primary stage, cooling stage, and the secondary phase. The critical parameter such as the temperature, time, and chamber pressure directly affects the process.
Lyophilization is carried out by the simple principle of sublimation. Sublimation is the process in which conversion of the substance from solid to vapor state without first passing through an intermediate liquid state.
INTRODUCTION TO LYOPHILIZATION:
The stabilization of the drug products through their shelf life is a challenge to the researchers. The physical, chemical nature of the drug products should remain the same as per standard specifications is very important. Most pharmaceutical drug products are unstable in their original forms.
Products like dry powder injectable. Lyophilized products are very difficult to store in their original form due to their drug degradation nature. The same drugs are used as and when required by reconstitution with sterile water for injection. The manufacturing of lyophilized products is a big challenge. If a failure in the batch happens it gets a huge impact on the financial / costing, hence the selected batches are very small and take on a trial and error basis.
While manufacturing the batches ICH Q8 guidelines for pharmaceutical development are to be taken into consideration and the batches are manufactured by using quality by the design tool. The potential risk to be identified, mitigated, investigated, and controlled to be implemented as per ICH Q9 guideline as Quality risk management and the quality of the product shall be maintained throughout the entire shelf life of the manufactured drug product as per ICH Q10 pharmaceutical quality system.
OVERVIEW OF LYOPHILIZATION PROCESS:
Lyophilization is also called a freeze-drying process. Lyophilization is the process of removal of ice or other frozen solvents from a material through the process of sublimation and the removal of bound water molecules through the process of desorption. This process is called sublimation, which transforms the ice directly into water vapor, without first passing through the liquid state.
The water vapor given off by the product in the sublimation phase condenses as ice on a collection trap, known as a condenser. The typical drying cycle is consists of three different stages: (1) freezing stage, (2) primary drying stage, and (3) secondary drying stage as described in the diagram.
DIAGRAM -A
Schematic diagram A represents the red and green lines that show the product and actual shelve temperature.
Basic Principle of Lyophilizer (Freez Dryer):
The steps required to lyophilize a product in a batch process are summarized as follows:
- Pre-treatment / Formulation
- Loading in Freeze Dryer (vials)
- Freezing (Thermal Treatment) at below atmospheric Pressure
- Eutectic temperature
- Primary Drying (Sublimation) under Vacuum
- Secondary Drying (Desorption) under Vacuum
- Pre-aeration and Stoppering (For Product in Vials) under Partial Vacuum followed by aeration
- Removal of Dried product from Freeze Dryer
The batch is manufactured under stated conditions and in the manufacturing tanks. The same batch is filtered through the 0.22µ filter. The same batch is taken for the filling activity. During the filling activity, all the environmental conditions are to be taken into consideration such as temperature, relative humidity, viable and non-viable particulate monitoring, pressure differential.
All the primary packing materials like vials, rubber stoppers shall be sterilized through the autoclave. In the filling stage half stoppering or semi stoppering to be done. This is a very important step at the filling stage of lyophilized products. The filled vials shall be transferred to the deep freezing chamber shelves. The operation shall be performed in the cleanroom having grade A/B. Before going to the lyophilization process, there is a need to set the defined parameters or working process, sometimes referred to as a Recipe. Individual time, pressure, and temperature are specified in each step. For every new product, there is a requirement for product recipe development.
In lyophilization, the first stage is the deep freezing in which the water is converted into the ice in vials by supercooling mechanism. The temperature changes from time to time. This stage is not more lengthy as the operation shall be completed in a few hours.
The primary drying is the phase in which the bulk water is removed from the product via sublimation of all of the free ice crystals. Organic solvents are also removed during primary drying.
Primary drying is a slow process conducted at cooler temperatures, safely below the product’s critical collapse temperature. All methods of heat transfer- conduction, convection, and radiation are employed during primary drying. The heat transfer induces the sublimation of ice in vials. The heat lost from the product as latent heat of sublimation will be supplied again from the chamber shelf. The primary drying stage required more time and economical patience.
In addition to the free ice that is sublimated during primary drying, a substantial amount of water molecules remain there that are bound to the product. This water is removed by desorption in secondary drying. Secondary drying is done at increased temperature because all of the free ice has been removed during primary drying, hence there are no chances of melting or product collapse. Some freeze dryers have the facility to remove the samples for moisture content determination in the secondary drying step based on which the drying step can be terminated. In this stage, the product temperature elevates higher temperature than the primary drying stage. The objective of secondary drying is to reduce the final residual water content to an acceptable level.
There are three different steps involved in the freeze-drying,
Partial Aeration (Pre- Aeration) In Lyophilization Process:
Once the secondary drying step is completed, partial aeration-also called pre- aeration is being performed usually using inert gas like nitrogen so as to leave some vacuum inside the vials. The compressed air is avoided in this operation.
Full Stoppering In Lyophilization Process:
Once the Partial Aeration is completed, the vials are fully stoppered by lowering the freeze dryer shelves one by one. This can be an automatic step in the freeze dryer recipe or can be performed in manual mode by pushing the button. Once the full stoppering is completed, the shelf position is restored to the original position.
Aeration In Lyophilization Process:
Final aeration is done usually with compressed air to bring the chamber to the atmospheric pressure. Condenser aeration is done after chamber aeration. The door of the freeze dryer is opened at the aseptic area side to unload vials. The vials are then sent to the capping machine for further operation. These above-mentioned steps are interdependent on each other one of the step failures impacted the further operation.
QUALIFICATION OF THE LYOPHILIZATION PROCESS:
Generally, qualification of the lyophilizer shall be performed as per the below-mentioned stages
URS (User requirements specification) of Lyophilization Process:
The URS comprises the basic user requirement aspect with respect to the product manufacturing and as per cGMP requirement.
DQ (Design Qualification) of Lyophilization Process:
It comprises the basic design consideration as per user requirements.
FAT ( Factory acceptance test) of Lyophilization Process:
This can be done at the manufacturer site, i.e. Pre-shipment critical test to be performed and verified.
SAT (Site acceptance test) of Lyophilization Process:
This can be done on-site. The verification of the actual shipment can be done with respect to any damage during the shipment.
Installation Qualification of Lyophilization Process:
The installation qualification shall be a performance to verify the actual machine is installed in a dedicated place in which the basic component verification, identification, leveling, alignment can be done.
Operational Qualification of Lyophilization Process:
in which the operational parameters shall be verified and the critical calibration component verified. The draft standard operating procedure shall be prepared in this stage.
Performance Qualification of Lyophilization Process:
In which the actual performance of the machine shall be verified.
Points to be considered during Lyophilizer Qualification:
1. Shelf Temperature In Lyophilization Process:
Ultimate shelf heating and cooling rates (+20°C to -40°C in ≤ 60 minutes) Ultimate high and low temperatures (minimum temp below -55°C after 30 min cooling and max temp above +80°C).
2. Condenser Cooling Verification In Lyophilization Process:
Maximum condenser cooling rate (Ambient to -40°C in ≤30 minutes) Ultimate condenser cooling test (Temperature ≤ -75°C after 60 minutes of cooling).
3. Vacuum Performance Verification In Lyophilization Process:
The time to achieve 100 µbar should be less than 40 minutes Ultimate vacuum of 5 µbar.
4. Main Valve Leak Rate Test In Lyophilization Process:
(0.01 mbar/Liter / Sec)
Main valve leak rate of 2 µbar in 30 minutes, Allowable rise = 0.05x1800 seconds /4360 liters = 0.0021 mbar.
5. Shelf Temperature In Lyophilization Process:
Setpoint Control at -40°C, 0°C, and +40°C ± 2°C.
6. Shelf Temperature Uniformity Verification -40°C, 0°C, and +40°C ± 2°C.
7. Vacuum Setpoint Control at 500, 100, and 50 µbar ± 5 µbar.
8. CIP Coverage Verification (Riboflavin Test).
9. SIP Effectiveness Verification (Sterilization and cooling).
10.System Leak Rate Test (0.01 mbar /Liter / Sec).
11. Allowable rise = 0.01x3600 seconds / 8140 liters = 0.0044 mbar
12. Shelf Ram Bellows Integrity Test.
Verify the pressure rise test of the bellows was performed to confirm the leak-tight to 0.01 mbar Liter / Sec. Record the pump downtime to 10 μbar here as the pass criteria.
13. Main Valve Bellows Integrity Test.
Verify the pressure rise test of the bellows was performed to confirm the leak-tight to 0.01 mbar Liter / Sec. Record the pump downtime to 10 μbar here as the pass criteria.
14. Condenser Capacity Verification
15. Condenser Defrosting Test
16. Freeze-Drying Cycle with Placebo
17. CIP and SIP
Advantages of Freeze Drying Lyophilization Process:
1. To dry heat-labile and water-unstable materials.
2. To get accurate, sterile dosing into the final product container.
3. To extend the shelf life or stability.
4. To preserve the biological activity of a product.
5. To eliminate the need for refrigerated storage.
Disadvantages of Freeze Drying Lyophilization Process:
1. To a Very complex process requires a high degree of automation and process control and men power with special skills and training for routine operation.
2. The total Capital cost of the Freeze Dryer equipment is very high.
3. Operating cost, regular maintenance, utilities, and spare parts cost of the freeze dryer is very high resulting in higher cost of the end product.
4. Freeze Drying is a very long process running for several days.
5. A least scope of saving the product in the condition of equipment failure during the running process.
REFERENCES:
1. S. L. Nail, S. Jiaang, S. Chongprasert, and S. A. Knopp, “Fundamentals of freeze-drying,” in Development and Manufacture of Protein Pharmaceuticals, S. L. Nail and M. J. Akers, Eds., Kluwer Academic/Plenum Publisher, New York, NY, USA, 2002.View at: Google Scholar
2. V. M. Zavala and L. T. Biegler, “Optimization-based strategies for the operation of low-density polyethylene tubular reactors: nonlinear model predictive control,” Computers & Chemical Engineering, vol. 33, 2009.View at: Publisher Site .
3. A. A. Barresi, V. Rasetto, and D. L. Marchisio, “Use of computational fluid dynamics for improving freeze-dryers design and process understanding. Part 1: modelling the lyophilisation chamber,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 129, 2018.View at: Publisher Site.
4. D. L. Marchisio, M. Galan, and A. A. Barresi, “Use of computational fluid dynamics for improving freeze-dryers design and process understanding. Part 2: condenser duct and valve modelling,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 129, 2018.
5. Recent Development of Optimization of Lyophilization Process Hidenori awasaki,1,2 Toshinori Shimanouchiand Yukitaka Kimura1Graduate School of Environmental and Life Science, Okayama University, 3-1-1, Tsuhima-naka, Kitaku, Okayama, Japan .
6. Lyophilization basic principle slide share by Dhaval surti.
Very good 👍
ReplyDelete100% leak test perform before freez dryer.
Thank you for giving valuable time for reading the post
DeleteLyophilization is a water removal process typically used to preserve perishable materials, to extend shelf life or make the material more convenient for transport. Lyophilization works by freezing the material, then reducing the pressure and adding heat to allow the frozen water in the material to sublimate. Ciron Drugs & Pharmaceuticals Pvt. Ltd. is the best known lyophilized injection manufacturers India. Ciron Pharma offers high-quality Lyophilized Products.
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