Optimization of a Manufacturing Process of Parenteral Lyophilized Drugs: Process Validation
Summary of dissertation for the degree of Master in Pharmaceutical Engineering Cláudia Rego Rodrigues1
1Instituto Superior Técnico, Universidade de Lisboa, Portugal claudiarodrigues@tecnico.ulisboa.pt
ABSTRACT
Exhibit batches were manufactured in 2011 and an ANDA with two presentations Product Y for Injection 5 g/vial Product Y for Injection 10 g/vial were submitted to authorities. The approval was guaranteed to Hikma by FDA on October 2018.
During launching batches of Product Y 5 g/vial it was noticed a high breakage rate, around 13,6%, representing a non-robust and not validated process. The improvement of Product Y 5 g/vial was essential and for that it was necessary to investigate the life cycle of Product Y. During the investigation it was concluded that the root cause of vial breakage was attributed to the fast-freezing phase. The fast freezing associated with the high filling volume caused a rapid and large expansion of the cake resulting in breakage problems.
In order to correct this problem, a Risk Assessment for the lyophilisation cycle between Product Y 5 g/vial and 10 g/vial was made. The lyophilisation cycle and the recipe of Product Y 10 g/vial was then adapted to the 5 g/vial resulting in a decrease to 0,7% of rejected vials resulting in the product’s validation. After correction the product was successfully launched.
Additionally, process improvement for efficiency purpose proposed a Line Transfer and a scale-up. For that, a Process Validation Protocol was designed and during these activities a decrease to 0,4% of broken vials was observed. With these results it was possible to confirm that our modifications were made successfully resulting in a robust process and independent from the line of the production.
Keywords
Lyophilization; Process Validation; Life Cycle; Optimization; Technology Transfer; Scale-up.
1. INTRODUCTION
Product Y Lyophilized powder for infusion is a new product developed by Research and Development Department of Hikma Pharmaceuticals at Jordan where the R&D is performed. Product Y is for intravenous infusion, a parenteral, indicated for treatment of severe infections and it is a generic transferred to Hikma Farmacêutica manufacturing facilities in Portugal. The formulation is a simple aqueous based formula that includes the API, an anti-gelling agent and water for injection (WFI), both disappear during lyophilization process.
1.1. Problem
In January of 2019 after the approval of FDA, Hikma Farmacêutica started to produce Product Y for Infusion USP, 5 g/vial and 10 g/vial and for launching the product in the US Market and consequently in order to validate the scale-up process, three Process Validation (PV) batches of 170 L in 400 L
tanks of Product Y for Infusion USP, 5 g/vial were manufactured at Liquid & Lyophilized Injectable Production Department- Line 1 at Hikma Farmacêutica Portugal.
To perform all process validation activities, it was necessary more two PV batches under the scope of PV protocol. The PV included compounding of the bulk solution, pre-filtration through a 1.2 µm filter, filtration through sterilizing 0.2 µm filter, filling, lyophilization, stoppering, capping and 100% visual inspection. In the end, a side by side comparison of finished product results was performed between 40 L batch (submission batch) and 170 L batches manufactured in Line 1 in order to evaluate the reproducibility of results or if any manufacturing constraint related to the scale up process is noticed.
The evaluation of the effects of the lyophilization on the quality of the filled vials, lyophilization uniformity and the evaluation of the results of 100% visual inspection of the vials was performed in three batches. During capping, in one of the inspection spots in the capper, it was noted that a significant percentage of cracked vials were rejected (between 13.6% and 8.8% of the unloaded quantity). After the amount of rejected vials was verify it was necessary to open a variance notice and the batch was immediately put into retention and therefore it was not possible to perform 100% visual inspection for the PV batches.
The significant percentage of cracked vials rejected turned the manufacturing process in a non-robust and unreproducible process becoming unvalidated. For that reason, the improvement of Product Y 5 g/vial as well as the identification of the root cause for the broken vials was necessary.
2. RELATED WORK
During the R&D investigation it was possible to confirm that the problem of vial breakage was in the freezing phase. The pattern of the crack (Figure 13) indicates that it is caused by expansion of the cake during freezing phase due to the fact that freezing occurs rapidly and in one shot shocking.
The fast-freezing makes the system of the matrix to expand suddenly without allowing the crystals, for enough time, to be shaped according to the vial size creating pressure on the edges and causing that bottomless breakage of the glass followed by a crack on the wall of the vial (Figure 13).
Large fill volumes are strongly correlated with higher percentage of vial cracks especially with fast temperature gradient. The strain on the vial's axial direction is significantly higher than the hoop direction typically resulting in bottom lens of the vial coming off (Jiang, 2007).
Figure 1. Typical Bottomless Breakage of the Product Y 5 g/vial Presentation during Lyophilization.
To follow this investigation, it was necessary to review all data collected and analyze the life cycle history of the product.
In 2011, after the R&D team prepared the formulation and studied the manufacturing process Hikma Farmacêutica decided to propose to the authorities a new product: Product Y for Infusion USP 5 g/vial and Product Y for Infusion USP 10 g/vial. To implement this product in the installations was defined activities intended to evaluate the manufacturing process for this product for US Market.
A Risk Analysis and Process Validation studies were made to provide evidence that a defined manufacturing procedure will consistently yield product meeting its predetermined specifications and quality characteristics.
Based on Process Validation, one submission batch of 40L was manufactured for Product Y for Infusion, USP 5 g/vial and one batch of 80L for Product Y for Infusion, USP 10 g/vial. The submission batches of Product Y for Infusion USP 5 g/vial (40 L) and Product Y for Infusion USP 10 g/vial (80 L) were prepared on 23rd October 2011 and 24th October 2011 respectively at Hikma Farmacêutica Portugal.
During the primary drying stage in submission batch for Product Y for Infusion USP 10 g/vial (80 L), the product was visually inspected through the sight glass located in both sides of the freeze dryer and signals of breakage were observed. However, the cycle was continued and after the unloading of the lyophilizer around 90% of the vials obtained were broken.
In order to completely overcome the problem of vials breakage, R&D department in Hikma Pharmaceuticals-Jordan started to investigate and to improve the problem appeared in the 10 g/vial submission batch. This research included different optimized cycles (additional trials #1 and #2) performed at R&D level and industrial scale. After all changes, when R&D create a robust cycle with no vial breakage a new submission batch of 80 L of Product Y for Infusion, USP 10 g/vial was applied.
Though, after unloading 7% of vial breakage was still verified.
In order to completely overcome the problem of vials breakage, additional tests were performed by R&D Jordan and a new modified lyophilization cycles were applied in 20 L trial batch (Trial #3 and Trial
#4).
The main reason for vial breakage was attributed to the fast-freezing rate applied – ramp down to -50 ºC in 6 hours - a factor that is especially important to take in consideration when applied on high concentrated solutions and large fill volumes, as the case of Product Y 10 g/vial. R&D main goal was to elongate the freezing time but not too long to minimize the pressure exerted on the wall of the vials.
All the modifications were due to prevent sudden expansion due to initial crystallization, reduce the time of the product at frozen state which would minimize the physical stress exerted by the frozen structure on the vial and add a hold step for the super-cooling temperature, in order to help arrange the crystals.
Forthwith, changes in the optimized cycle (having as reference the cycle applied in trial #4) were successful in enhancing the mentioned product characteristics: crystallization, cake dryness, water content and reconstitution time. The changes applied are not anticipated to cause vial breakage since the phenomenon is directly affected by freezing stage and primary drying. Moreover, this cycle was challenged by loading 100 mL filled vials along with 60 mL ones and no vials breakage was observed by the end of the cycle.
Based on the results obtained from all the trials, scale-up and submission batches, it was recommended to proceed with the preparation of the submission batch of Product Y 10 g/vial applying the following lyophilization cycle:
Phase No. Process-Phase Phase Time (h:m) Set Temp. (ºC) Vacuum (µbar)
1. Loading (Precooled shelves) --:-- +5
2. Freezing OFF
06:00 -20
08:00 -20
06:00 -45
03:00 - 45
Total Cycle Time 138:00 hours
Table 1. Final Lyophilization cycle parameters to be applied for FDA submission.
After all data collection, Hikma Farmacêutica wrote, in 2012, a Data Compilation Report for the submission of Product Y for Infusion, USP 5 g/vial and Product Y for Infusion, USP 10 g/vial where the critical process steps in the manufacturing process were evaluated according to the Risk Assessment.
The compounding of the bulk solution formula, bioburden reduction filtration through a 1.2 µm filter, final filtration through a 0.2 µm filter, filling, lyophilization and inspection were accepted in October, 2018 when the FDA gives the approval for the manufacturing process for Product Y for Infusion, USP 5 g/vial and 10 g/vial.
3. PRACTICAL CASE
After the review of all data collected about Product Y and an exhaustive investigation of the life cycle it was possible to confirm that the problem was in the freezing phase similar what happened in the past with the 10 g/vial form. In the freezing phase, it happens quickly the icing of the lyophilized cake and this step causes an expansion in the cake volume.
In order to improve and solve the cause of this type of breakage during lyophilization attributed to the freezing phase it was proposed to adjust the recipe (LYC018) of Product Y 5 g/vial to become similar to the freezing step of the Product Y 10 g/vial, already improved in the past, in which the freezing pattern is gradual rather than shocking the matrix sudden and with very low temperature.
To adapt the recipe of Product Y 10 g/vial in the recipe of Product Y 5 g/vial it was necessary to perform a Risk Assessment where all the risks were evaluated.
Approved 10 g/vial lyo cycle Approved 5 g/vial lyo cycle Time
(h:min)
Temp (°C)
Vacuum (µbar)
Time
(h:min) Temp (°C) Vacuum (µbar)
Freezing
6:00 -20
-
8:00 -20
6:00 -45 5:00 -50
3:00 -45 4:00 -50 -
Table 2. Approved freezing phase parameters.
In terms of the lyophilization cycle, Product Y, USP 10 g/vial recipe presentation is considered the worst-case, having the double of the fill volume (and the same container than in Product Y 5 g/vial) and higher stress and impact on the Primary Package, namely the vial itself. However, the 10 g/vial presentation shows not suffer from breakage as the 5 g/vial.
Upon reviewing the Lyophilization Cycle for both strengths; it was found out that the 10 g/vial has a gradual freezing pattern in the cycle, while the 5 g/vial lacked this, but rather it was a sudden and much fast freezing without any intervals.
It was extrapolated that by applying the same freezing rates and pattern to the 5 g/vial this vial breakage will be eliminated, and the frozen matrix will behave similarly to the 10 g/vial (as both share exactly the same formulation).
Since both formulations share the same bulk solution, container closure system – both are filled in a 100mL molded vials- and they only differ in the fill volume it was concluded during the Risk Analysis that the adaption of the freezing recipe of Product Y 10 g/vial in the recipe of Product 5 g/vial has no impact in the quality of the product and manufacturing process.
The modifications made in the freezing step was to decrease the impact of lyophilization on the reject quantity. No changes were made to the rest of the recipe, primary and secondary drying, for Product Y for Infusion, USP 5 g/vial.
Approved 10 g/vial lyo cycle Approved 5 g/vial lyo cycle Improved 5 g/vial lyo cycle Time
(hr:min)
Temp (°C)
Vacuum (µbar)
Time (hr:min)
Temp (°C)
Vacuum (µbar)
Time (hr:min)
Temp (°C)
Vacuum (µbar)
Loading - +5 - - +5 - - +5 -
Freezing
6:00 -20
-
6:00 -20
-
8:00 -20 8:00 -20
6:00 -45 5:00 -50
-
6:00 -45
3:00 -45 4:00 -50 3:00 -45
Table 3. Lyophilization cycle parameters comparison for Product Y 5 g/vial (Current and Improved Freezing Phase) and 10 g/vial.
After all the changes were made, an evaluation of 100% inspection was done and compared with another PV batch of Product Y 5 g/vial that was lyophilized using the approved freeze-drying cycle before the improvement.
APPROVED LYO CYCLE AS
PER LYC018 IMPROVED FREEZING PHASE CYCLE
Total vials 4779 4980
Total of broken/cracked vials rejected 652 36
% of total of broken/cracked vials rejected 13.6 0.7
Table 4. Side-by-side Inspection results of batch of Product Y for Infusion USP 5 g/vial.
From the evaluation of the analytical data presented from the manufactured batches of Product Y for
phase cycle improvement. As it can be observed from Table 4, it was noticed a decrease of cracked vials from 13.6% to 0.7% in the capping loading process.
4. LINE TRANSFER AND SCALE-UP FOR PRODUCT 5 G/VIAL – A PROCESS VALIDATION After the successful improvements, it was purposed a Line Transfer from Line 1 to Line 9 and a scale- up from 170 L to 310L batch size of Product Y for Infusion USP 5 g/vial for US Market. For that, it was necessary to perform a Process Validation Protocol to define the activities and sampling requirements intended to evaluate and validate the scale-up and the Line Transfer.
In order to validate the scale-up process, three Process Validation (PV) batches of 310 L of Product Y for Infusion USP 5 g/vial were manufactured at Line 9 in Hikma Farmacêutica S.A. One PV batch was for submission purpose and upon approval of the process, two additional PV batches were manufactured to complete the process validation activities.
Hikma Farmacêutica, S.A validation program includes the validation of processes used in manufacturing pharmaceutical products. In the case of Product Y for Infusion USP 5 g/vial, this includes compounding of the bulk solution, pre-filtration through a 1.2µm filter, filtration through sterilizing 0.2µm filter, filling, lyophilization, stoppering, capping and 100% visual inspection. The filtered bulk solution was filled into a 100 mL vial presentation.
The critical process steps in the manufacture of Product Y for Infusion USP 5 g/vial were evaluated based on Risk Management Tools.
Evaluation of the effects of Lyophilization on the quality of the filled vials and lyophilization uniformity
The process validation batches were lyophilized as per lyophilization cycle in SOP#LYC018.
Lyophilizer from Line 9 was considered the worst case from a loading perspective because the loading and unloading at Line 9 is automatic while in Line 1 is manual despite reduces aseptic handling. Both lines have similar lyophilizers however the controls and also the condensers capacity are different.
To evaluate the quality and uniformity of lyophilization, vials were collected from the freeze-dryer for analysis (appearance of the cake, reconstitution time and water content) from the indicated positions presented on Figure 2 and properly labelled accordingly to correlate the results with the position in the lyophilizer.
Notes:
a) Each batch will fill approximately 10 shelves per lyophilizer.
b) Samples from three shelves per lyophilizer should be
collected/tested.
c) If the last shelf is not fully loaded collect samples from the previous one.
d) All vials must be capped (manually or using the capper).
Middle shelf First shelf
Last Shelf
Figure 2- Loading positions for PV batches and samples collection.
Based on the results evaluated from samples taken from several lyophilizer positions, it can be observed that all results are within specifications and aligned between them, which means that there is uniformity within lyophilizer. Additionally, the water content results show that the lyophilization cycle is efficient, properly drying the product. Moreover, the water content results for finished product obtained are well below the acceptance criteria and aligned when compared with the results of the previous manufactured batches of Product Y for Infusion USP, 5 g/vial with 170L batch size in Line 1.
Despite the lyophilizer from Line 1 and Line 9 are different as also the controls and the capacity it was possible to confirm with the results from this evaluation that there is uniformity within lyophilizers.
Evaluation of 100% inspection
Lyophilized vials from the process validation batches were submitted to 100% visual inspection for defects and particles after being capped. The 100% inspection is executed using the automatic inspection machine. From the results, it can be concluded that the percentage of total number of vials rejected with defects is between 0.1% and 0.6% of the total number of vials submitted to capping and 100% inspection showing all results are conforming.
Successful process validation studies provide evidence that a defined manufacturing procedure will consistently yield product meeting its pre-determined specifications and quality characteristics. Each activity is described in detail as are sampling requirements needed to complete the evaluation.
From the manufacturing process and in-process controls (beginning, middle and end) and from finished product testing and side by side comparison (Attachment 4), it can be concluded that the process is capable of producing a product within specifications with scale up from 170L to 310L and line transfer from Line 1 to Line 9.
After the lyophilization during the PV activities for the Line Transfer and scale-up it was analyzed the number of broken vials (Table 5).
BATCH #1 BATCH #2 BATCH #3 BATCH #4
vials rejected
Table 5. Percentage of cracked vials reject after Scale-up and Line Transfer.
After scale-up and Line Transfer activities it was possible to verify that all changes done before in the lyophilization cycle were successful and without negative impact in the number of broken vials. Additionally, the quality of the final product was kept. In short, the results shown that we are facing a robust and validated process who is reproducible in Line 9 with a batch size of 310 L and possible to launch in the market with high quality.
5. LAUNCHING
Fill Volume Price
Product Y 5 g/vial 10.52 €/vial
Product Y 10 g/vial 20.45 €/vial
Table 6. Launching for Product Y for Infusion USP.
The Product Y 10 g/vial is valued as 20.45 € per vial and the presentation of Product Y 5 g/vial as 10.52 €/vial.
After the improvement made in Product Y 5 g/vial it was possible to reduce the percentage of breakage vials from 13.6% to 0.7% which means a decrease in 12,9% of breakage vials per batch.
The theoretical value per batch is as described in Table 5.
Line Minimal Quantity (units) Maximum Quantity (units)
1 5 573 5 573
9 10 163 10 163
Table 7. Approved Batch Sizes for Product Y for Infusion, USP 5 g/vial.
After all the modifications, it was measured the percentage of good vials per theoretical batch that was possible to rise up and calculated the value possible to monetize per batch: 7 563€ for Line 1 and 13 792€ for Line 9. In one year if we produce 25 batches in Line 1 and 25 batches in Line 9 it is possible to increase for 533 875€ per year.
For the future, one Line will be dedicated for Product Y and if in half-year (26 weeks) it is produced Product Y 5 g/vial two times per week in Line 9, for example, with this modification it will be possible to improve in 717 184€.
The values represented above do not represent a big impact for the company. However, with the improvement of Product Y 5 g/vial it was possible to validate the manufacturing process and consequently launch the product for the US Market.
6. CONCLUSION
In January, 2019 during the PV of Product Y USP, 5 g/vial it was not possible to perform 100%
inspection for the PV batches because it was noticed a significant percentage of cracked vials rejected during capping process (between 13,6% and 8,8%).
The significant percentage of cracked vials rejected turned the manufacturing process in a non-robust and unvalidated process. For that reason, the improvement of Product Y 5 g/vial as well as the discovery of the root cause for the broken vials was necessary.
To follow this investigation, it was necessary to review all data collected and analyze the life cycle history of the product.
The root cause of the breakage problem was attributed to the fast-freezing rate applied during freezing phase on the lyophilization cycle. The fast-freezing makes the product to expand suddenly without allowing the crystals, for enough time, to be shaped according to the vial size creating pressure on the edges and causing the bottomless breakage of the glass.
In order to optimize the lyophilization cycle of 5 g/vial form and based in a Risk Assessment it was purposed to adapt the freezing recipe of 10 g/vial in the recipe of 5 g/vial. Changes were made and the improvement of lyophilization cycle, namely, the freezing phase was successfully and it was possible to decrease the percentage of vial breakage from 13.6% to 0.7% of vials per batch converting in a validated process. After correction the product was successfully launched in the US Market.
Additionally, for the improvement of efficiency, a Line Transfer from Line 1 and Line 9 and a scale-up to 310 L were proposed and it was necessary to perform a Process Validation where the critical steps were analyzed. The PV results showed no negative impact resulting in an effective Line Transfer and scale-up. It was also possible to verify a decrease to 0,4% of broken vials was observed. With these results it was possible to confirm that our modifications were made successfully resulting in a robust process and independent from the line of the production.
Acknowledgements
A very special gratitude goes out to all down at Hikma Farmacêutica for helping and providing the internship. With a special mention to Samuel Camocho the Lyophilization Plant Manager and all the team in general. It was fantastic to have the opportunity to work during my internship in your facilities.
What a cracking place to work!
I am also grateful to Professor Carlos Manuel Faria de Barros Henriques for the guidance during the executation of the dissertation.
And finally, last but by no means least, my family and friends.
Thanks for all your encouragement!
References
Lyophilization Cycle Improvement Protocol (PRD1/PRO/0001/19)
Product Y 5 g/vial and 10 g/vial Development Report (NPD/REP/0029/11 and its Addendum, and NPD/REP/0039/11)
Product Y 5 g/vial current lyopilization cycle SOP# LYC018 Product Y 10 g/vial current lyophilization cycle SOP# LYC018
Product Y 5 g/vial improved freezing phase lyophilization cycle PRD1/PRO/0001/19
e Jiang, et al. “Mechanistic Studies of Glass Vial Breakage for Frozen Formulations. I. Vial Breakage Caused by Crystallizable Excipient Mannitol.” PDA Journal of Pharmaceutical Science and Technology, vol. 61, no. 6, Nov. 2007, pp. 441–451, journal.pda.org/content/61/6/441. Accessed 31 Oct. 2019.
