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Technology in safe transfer of monoclonal antibody PH

Technology Transfer Module
Assignment Criteria.
Product PH123 is being transferred from sending site ABC Pharma to receiving site Phantom Pharmaceuticals.
As the Project Manager, you are required to:
- Carryout a critical analysis (incorporate a gap analysis and risk assessment) on transferring the process between the sending and receiving sites
- List additional studies/sub projects that you consider a requirement of the transfer process
- List the Critical Process Parameters for the following process steps
- Formulation
- Sterile filtration
- Filling
- Design a Process Validation protocol for the validation of this product for the steps listed in Part 3, paying particular attention to test procedures and acceptance criteria
Answer
Critical analysis of the transferring process
The moot purpose of the transferring process is to send a 20ml sterile solution of PH-123 drug product from the manufacturing site of ABC pharmaceuticals to Phantom pharmaceuticals without any considerable alteration of the drug product except some minor process adjustments to be compatible with new process transfer equipments. As the types of transfer are limited only to release, it is imperative to review all the associated activities from capital investments to the vulnerable alterations of transfer strategies in accordance with the potential regulatory measures in order to identify the discrepancies of the sending and recipient site conditions.
Gap analysis
Facility and equipment: It has been observed that, the temperature in which ABC Pharmaceuticals is sending the PH-123 sterile solution is allowed to vary within 18 to 20 where the recipient site has been able to manage an ambient temperature of 2 to 8. Furthermore, it is very evident from the product storage specifications that the sterile solution is highly in need to be kept in cold room prior to the upcoming process. In this regard, it can be mentioned that this flagrant discrepancy might lead the solution to be contaminated and loose its desired effectiveness (Shukla and Gottschalk, 2013). Moreover, torrid storages are typically very humid and might transcend the requisite relative humidity of less than 50%, which might bring the same consequences.
Cleaning and Sterilisation: The equipment that is typical to use in order to accomplish the task of cleansing and sterilization properly is the Steris Autoclave-stopper sterilisation. In the receiving site, the desired purpose has been accomplished through ZFORM Stopper processer. In this regard, that might be an issue while employing equivalent apparatus while heeding on several aspects of sterilisation. Thus, it requires a validation process to be conducted.
Compounding: As it is the prime requisite to make a buffer solution up to 600L BMV1 Buffer Vessel in a bottom mounted magnetic mixer; several safety measures needs to be taken especially in order to carry out pressure test of the Buffer vessel while keeping all the connections at 2 barg. In the compounding vessel of the bottom mounted magnetic mixer, the Silicon tubings need to be connected properly with the GHT connections in the bottom outlet.
Risk Assessment
In this regard, the vulnerable origins of risk can be emerged out of the robustness of process. Since the specimens of PH-123 are intensely sensitive to minor alterations of any excipient sources and several other vulnerable process variations, it has been discovered studying prevalent cases that the former does not cause any considerable issues that are adverse. Though occasional process issues are because the severity as a consequence of risks, it has been observed that it does not cause any material loss or significant downtime issue.
The other origins that might evoke reasons for potential risks can be categorized as issues regarding the quality of the specimens including the notion of stability. The cardinal issues that can arise and vulnerable to be incorporated in the paradigm of risks are the issues regarding legislative regulation sand recall. In this regard, several measures can be recommended that can be categorized as;
- Direct compression
- Extrusion
- Terminal Sterilization
- Fluid bed granulation
Sub Projects:
Temperature Study
In the incipient phase of production of PH-123, it has been observed that the nascent specimen need to be kept in an ambient temperature not more than 20 degree centigrade. When the receiver site receives the specimen, they are always recommended to maintain a temperature of cold room that is allowed to vary from 2 degree to 8 degree centigrade. This is imperative in other terms of storage since the storehouse has been constrained by certain conditions related to relative humidity. For instance, in order to sustain the specimen with its requisite effectiveness, it is a cardinal criterion to keep it in a relatively less humid place since where the relative humidity level must not exceed the 50%. Thus, it is imperative to maintain the requirement of temperature regarding the storage since excess humidity is the inevitable by product of excess temperature (Keen et al. 2014).
Furthermore, temperature is also a cardinal component in terms of thawing process. Since the integral process of thawing in extremely temperature sensitive, it is imperative to preserve the specimen while abiding by its temperature requirements in order to accomplish desired results. Visual inspection of the specimen being thawed is further used as a trustworthy indicator of the specimen being in the desirable effectiveness, it is imperative ensure the successful conduction of thawing process while confirming a complete thaw.
In summary, temperature is a cardinal component in this regard since it might cause the desire drug to contaminate and lose the desired characteristics. Furthermore, it is also imperative for the process to be desirable one and one of the pivotal ways to ensure this is to retain the desired temperature.
Mix study
It is also need to conducted with sincere precision since it is imperative to expect to expect desired results from the specimen. On the other hand, the mixing of the drug substance that ensures the successful completion of the further tasks associated with it. Mixing study typically emphasizes on the proportional blend of sterile solution with the primordial specimen. Moreover, it intends to specify the requisite solution of the buffer solution and the fixes the stoppers in order to let the primordial specimen function expectedly. In the best industrial practice, the buffer solution is typically made of Sodium Chloride, Sucrose, Sodium Phosphate Diabasic Anhydrous and Sodium Monobasic Monohydrus. On the other, the reputed industrial practitioners typically use a 20mm coated stopper. It has been stated since the sending sites typically get a massive order of 5000 vials at a same time.
Critical Process Parameters
These parameters of the underlying transfer process are considered as critical since these measures are essential to undertake in order to prevent the specimen from contamination that might cause a considerable loss of effectiveness of the product. In these regard, the requirements need to sincerely conducted in order to ensure proper completion of the entire process. These measures need to be maintained thoroughly across the transfer of the materials from the sending site to the receiving site. For instance, in the shipment phase, in most of the cases the recipient did not inspect the bottle completely, which can cause severe causes of specimen contamination.
Formulation
Drug products typically consist of two different products against the notion of formulation. In this regard, the receiving site needs to provide two separate P section against every formulated products. For instance, the illustrative information of the drug products along with the reconstitution diluents must be presented by the sending site in two different P sections. On the same note, it can also be maintained that various closure configurations of the container coupled with fills and strengths must be included in the prevalent P sections. For instance, if a non-preserved formulation package of prefilled syringes and unit dose vials coupled with a preserved formulation package of multidose vial needs to be presented in two separate P sections. Furthermore, on the same note it can be stated that, 1-day and 7-day transdermal durg delivery system can be adapted in order to modify the released products with different release mechanisms.
Sterile filtration
This is also a cardinal process parameter since any deviation of the proportion of constituents might lead to contamination of the ultimate specimen, which eventually paves the entire specimen to lose its desired effectiveness. In regards with the current project, PH-123, which is a human monoclonal antibody, is industrially available as a 20ml sterile solution along with an infusion containing 20mg of the specimen for every litre of sterile.
In accordance with best industrial practices, there are 8 governing elements that has been utilized to validate sterile filtration. These became evident from the underlying picture.
Figure: Overview of Sterile Filtration
Source: Humbert et al (2016)
Filling
It is also one of the cardinal factors to conduct a transfer process properly since the principal materials along with the stoppering vials are integral components of the same. In order to ensure proper release of those elements, the receiving site needs to maintain a proper demeanour to each of the elements associated with filling and stoppering vials. For instance, the receivers are recommended to use recipe SFF2 in order to train the sterile filtration while instantly purifying the filling line. Furthermore, in order to drain the craps of filtration, a barrier filter XLP65 needs to be incorporated (Heider, et al. 2014).
Process Validation Protocol
Prospective process
Use of monoclonal antibodies goes through a complex production process and it exceeds the laboratory productions. The production systems have been evolved through various production processes and the alternative processes are emerging. The scale-up by the use of suspension cells has more efficient production method that are available for the cultivation of the cells. Suspension production has another advantage and that is it provides a system which is bioreactor with a large area of cell adhesion (Sharma, 2016).
Critical parameters
Serial Number | Raw Materials | Specification | Units | Quantity |
11516188 | Mannitol USP, EP | NA | NA | NA |
11407273 | Glycine USP, EP | NA | NA | NA |
11818766 | Sodium Phosphate Dibasic Anhydrous USP, EP | |||
00910048 | Ph-123 DS | NA | NA | NA |
11818766 | Sodium Phosphate Monobasic Monohydrate USP | NA | NA | NA |
64205817 | 25ml Type 1 Tubular Vial | NA | NA | NA |
TBD | S-87-1 Bromobutyl Stopper 4432/50 B2-O4 | NA | NA | NA |
Material and methods
There are different types of bioreactors, which are submerged in the mammalian cell, and they are stainless steel stirred tank bioreactors, air lift reactors along with disposable bioreactors (Humbert et al. 2016).
Machineries
Stainless steel stirred tank bio reactors
These are considered the most consolidated type of bioreactors which are used in the industrial production purpose. It is consisted of baffled stirred tanks which are linked with motor systems. The advantage of the machinery is it allows a wide range of flexibility of working volumes.
Air-lift reactors
Air-lift reactors are broadly used for the industrial production. The reactor is consisted of tanks that has a bubble column inside. This creates a constant gentle mixing of the medium as well as the proper culture aeration including the annulling part of the shear stress.
Along with the mentioned machineries, some of the other machineries are disposable bioreactors and roller bottles (Sharma, 2016).
It is necessary to implement few changes in the designing process for small production volumes.
Manufacturing/Packaging Facility | |||
Facility/Conditions | Sending Site | Receiving Site | Comments/Changes |
Temperature | 20ºC ± 2ºC | 2-8℃ | Cold |Room Reqruired to carry out the process |
Humidity | ≤ 50% RH | ≤ 40% RH | The humidity needs to be in accordance with the requirement |
Room Classifications | Compounding: Grade C Filtration: Grade C Filling: Grade A | Compounding: Grade A Filtration: Grade A Filling: Grade C | The grade requirement needs to be maintained and must be carried out in the mentioned temperature |
Table 2.1
Manufacturing Equipment | |||||
Sending Site | Receiving Site | Comments | Gap analysis | Risk aseesment | |
Equipment – Name/Type | Equipment – Name/Type | ||||
Cleaning / Sterilisation | |||||
Steris or Amsco Autoclave | |||||
Steris Autoclave – Stopper sterilisation | ZFORM Stopper Processor ZF2 | Equivalent equipment performing the same process. Sterilisation validation to be completed | NA | Moderate | |
Capsolut washer | Bosch vial water | Sterilisation validation to be completed | NA | High | |
Compounding | |||||
500L Stainless Steel jacketed tank XYZ with top mounted mixer – Buffer prep | Buffer Make Up 600L BMV1 Buffer Vessel (bottom mounted magnetic mixer) | CIP (Clean in Place) vessel and lines ( If Clean status >7 days) | NA | Moderate | |
400L Stainless Steel Jacketed Formulation Product Vessel No. 2 – Top mounted mixer | Compounding Vessel CK03 (bottom mounted magnetic mixer) | Install Vent filter on Buffer vessel. | NA | Moderate | |
400L Glass lined vessel GL1 – top mounted mixer | Transfer Tank TK03 (bottom mounted magnetic mixer) | CIP vessel and lines ( If Clean status >7 days) | NA | High | |
Sauber Peristaltic Pump Model 10 | Millipore Filter FPXZTP3 | Install Vent filter on Transfer Tank SIP ofvessel and lines | NA | Moderate | |
2 x Millipak filters | Transfer Tank TK03 | NA | Moderate | ||
Filling / Capping | |||||
Bausch & Strobel Washer | Barrier filter XLP65 | Install Barrier filter XLP65 on drain | NA | High | |
Bausch & Strobel Depyrogenation Tunnel | Filter FPXZTP3 | Stoppers are washed & sterilised in the ZFORM stopper Processor ZF2 | NA | Moderate | |
Bausch & Strobel Pump/Piston Filler | Sterile Filter housing | filled to a specification of 8ml ± 3% into 10ml vials using the Bosch Time Pressure Filler BF1). | NA | Moderate | |
West Capper | filled to a specification of 8ml ± 3% into 10ml vials using the Bosch Time Pressure Filler BF1). | NA | low | ||
-70degC Freezer | filled to a specification of 8ml ± 3% into 10ml vials using the Bosch Time Pressure Filler BF1). | Note Dublin currently have no freezer | High | ||
Inspection | |||||
N/A | |||||
Table 2.2
Formulation | ||||||
Unit Formula | ||||||
Sending Site | Receiving Site | |||||
Material ID No. | Material Title | mg/vial | Material ID No. | Material Title | mg/vial | Comments |
21300000 | Water for Inj USP, EP | N/A | 10098 | Sodium Chloride | NA | |
11516188 | Mannitol USP, EP | 36mg | A0092 | Sucrose | 30mg | |
11407273 | Glycine USP, EP | 1.36mg | 305A004 | Sodium Phosphate Diabasic Anhydrous | 2.76 mg | |
11841187 | Sodium Phosphate Dibasic Anhydrous USP, EP | 1.04mg | 98935 | Gerresheimer Glass | 10ml | |
11818766 | Sodium Phosphate Monobasic Monohydrous USP, EP | 0.36mg | 305A004 | Sodium Monabasic Monohydrous | 0.63 mg | |
00910048 | PH123 Drug Substance (DS) | 20mg | 305A004 | Sodium Monabasic Monohydrous | 10 mg |
Bill of Materials | ||||||
Sending Site | Receiving Site | |||||
Material ID No. | Raw Material Title | Manufacturer | Material ID No. | Raw Material Title | Manufacturer | Comments |
11516188 | Mannitol USP, EP | JT Baker (Mallinckrodt) North Carolina | 097865 | Mannitol USP, EP | Merck, Germany | Change to supplier. Same grade of material. USP/EP Verification testing will be completed |
11407273 | Glycine USP, EP | JT Baker (Mallinckrodt) North Carolina | 10098 | Glycine USP, EP | Merck, Germany | Forward to the supplier about upgraded material; USP/EP verification test need to be completed |
11841187 | Sodium Phosphate Dibasic Anhydrous USP, EP | JT Baker (Mallinckrodt) North Carolina | 305A004 | Sodium Phosphate Dibasic Anhydrous | Merck, Germany | USP, EP verification test need to be completed |
11818766 | Sodium Phosphate Monobasic Monohydrate USP | JT Baker (Mallinckrodt) North Carolina | 10032 | Sodium Phosphate Monobasic Monohydrate | Merck, Germany | Same grade material; USP test is required |
00910048 | PH-123 DS | PhaSys Germany | 00910049 | PH-123 DS | North Carolina | DS test need to be completed |
64205817 | 25ml Type 1 Tubular Vial | Gerresheimer Glass Inc. Germany | 98935 | 25ml Type 1 tubular glass vial | Gerresheimer Glass Inc. Germany | Sterile filtration train using recipe SFF2 |
TBD | S-87-I Bromobutyl Stopper 4432/50 B2-04 | West Pharmaceutical Services New Jersey | 20336 | S-107-J/50 Bromobutyl Stopper | West Pharmaceutical services, New Jersey | Sterile filtration train using recipe SFF2 |
Various | 20mm Flip-Off Aluminium Seals | West Pharmaceutical Services New Jersey | 90337 | 20MM Aluminium red Flip-off Overseal | West, Germany | |
Not available | Millipore Millpak Filter | Millipore France |
Manufacturing Steps | ||
Sending Site | Receiving Site | |
Current Manufacturing Steps | Proposed Manufacturing Steps | Comments/Changes |
Buffer Formulation | ||
Clean all parts in Capsolut parts washer | SIP the transfer tank using cycle X15 | |
Clean Tank XYZ using recipe no.2 on PMS | On completion of SIP, connect silicone tubing previously attached to bottom of compounding tank to the inlet of the Millipore Filter FPXZTP3 on Spray Nozzle 2 on Transfer Tank TK03 | sterile bulk solution is aseptically filled to a specification of 8ml ± 3% into 10ml vials using the Bosch Time Pressure Filler BF1) |
Steam Tank XYZ using recipe no.2 on PMS | For storage of solution pressurise contents to 0.1 barg with N2 blanket. | Nitrogen pressure of 10psi, |
Add WFI to 90% of final volume | The hold time from the time from the end of product transfer into the Transfer tank to the end of Capping is 48 hours | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Set mixer speed to 200rpm | For storage of solution pressurise contents to 0.1 barg with N2 blanket. | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Add the Mannitol and mix at 200 ± 20rpm until fully dissolved | Add the Glycine and mix until fully dissolved | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Add the Glycine and mix at 200 ± 20rpm until fully dissolved | Add the Glycine and mix until fully dissolved | Mixing speed in Dublin to be determined post mixing studies |
Add the Sodium Phosphate Monobasic Monohydrate and mix at 200 ± 20rpm until fully dissolved | For storage of solution pressurise contents to 0.1 barg with N2 blanket. | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Add the Sodium Phosphate Dibasic Anhydrous and mix at 200 ± 20rpm until fully dissolved | Add the Glycine and mix until fully dissolved | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Adjust to final weight with ambient (15ºC to 30ºC) WFI | For storage of solution pressurise contents to 0.1 barg with N2 blanket. | NMT 96 hrs from end of preparation to final addition to the bulk solution |
Take sample for pH and Osmolality | NA | NA |
IPC All excipients visually dissolved pH: 7.3 – 7.5 Osmolality: 110 – 140 mOsm/kg | NA | NA |
Store filtered buffer at room temperature at 2ºC - 8ºC for not more than (NMT) 48 hours | NA | NA |
Batch Manufacture | ||
Existing Process | Proposed Process | Impact / Action |
Clean all parts in Capsolut parts washer | Same | No change |
Clean Compounding Tank No. 2 using recipe no.2 on PMS | Using recipe no.5 on PMS | Effective |
Steam Tank No. 2 using recipe no.2 on PMS | Using recipe no. 3 PMS | Effective |
Remove the required quantity of PH-123 DS from -70ºC storage and transfer to 2ºC - 8ºC storage | Same | NA |
Thaw PH-123 for not less than (NLT) 56 hours and use within 152 hours from time API is moved from 2ºC - 8ºC storage | Thaw PH-123 for not less than (NLT) 36 hours and use within 152 hours from time API is moved from 3ºC - 9ºC storage | Effective |
Slowly pour the thawed API into the compounding vessel. If more than one bottle is poured into the vessel, mix gently for 10 minutes post additions, avoiding foaming | Same | NA |
Take a 15ml sample and determine protein concentration (UV) | Same | NA |
Calculate 90% target weight as per batch record | Same | NA |
Using peristaltic pump at a speed setting of 3 dilute to 90% of target weight with buffer solution. | Using Nitrogen, transfer buffer from Buffer Tank BMV1 to Compounding tank CK03 until 90% of target weight is achieved | Dublin will use pressure transfer. Buffer and compounding tanks are multi-use and cleaning verification / validation to be determined |
Take another sample and determine protein concentration(UV) | ||
Calculate the final weight as per the batch record and adjust to final bulk weight using the buffer solution using a peristaltic pump at a speed setting of 3 | ||
Take protein concentration (UV, density, pH and Bioburden samples | ||
IPC All excipients visually dissolved pH: 7.2 – 7.6 Density: For information only Bioburden: NMT 10cfu/100ml | ||
Clean all parts in Capsolut parts washer | ||
Clean Glass lined vessel GL1 using recipe no.2 on PMS | ||
Steam Glass lined vessel GL1 using recipe no.2 on PMS | ||
Filter the solution from Compounding Tank No. 2 through a 0.22µm Millipore millipak filter into Galss Lined Vessel GL1 | ||
Sterilise stoppers at a Sterilisation temperature of 122°C, for 40 minutes, drying for NLT 240 minutes at a temperature of 100°C, followed by pressure drying (1100mbar) and cooling for 30 minutes | ||
Submit bulk sterility samples for testing | ||
Verify that the Sterile Filtration train and Filling line have been Cleaned (CIP) and Sterilised (SIP) as per SOP ABC-123 | ||
Fill 20ml of the liquid into 25ml washed / depyrogenated vials. | ||
Cap the batch with flip tear off seal | ||
Sample batch for finished product testing | ||
Manually inspect the batch | ||
Pack inspected product in nested cells | ||
Batch Formula | ||||||
Sending Site | Receiving Site | |||||
Material ID No. | Material Title | 20,000 Batch Size | Material ID No. | Material Title | 25,000 Batch Size | Comments |
21300000 | Water for Inj USP, EP | *200Kg | Dublin will manufacture a slightly larger batch size | |||
11516188 | Mannitol USP, EP | 1.44Kg | 9874561 | Mannitol USP, EP | 1.8Kg | |
11407273 | Glycine USP, EP | 54.4g | ||||
11841187 | Sodium Phosphate Dibasic Anhydrous USP, EP | 41.6g | ||||
11818766 | Sodium Phosphate Monobasic Monohydrous USP, EP | 14.4g | ||||
00910048 | PH-123 DS | 800g for 20mg/vial | ||||
Total Weight | 400Kg | 500Kg |
Primary Packaging Components | ||||||
Current - Sending Site | Proposed - Receiving Site | |||||
Spec. No. | Description | Supplier | Spec. No. | Description | Supplier | Comments |
64205817 | 25ml vial, unprinted tubing, USP Type 1, B-corkage | Gerresheimer Glass Inc. | ||||
65003727 | 20mmseal, Green Flip-off, Matte finish, 8 bridge | West | 1112432 | 20mm seal, Green Flip-off, Matte finish, 8 bridge | West (Germany) | Same supplier. Different site of Manufacture |
TBD | 20mm Stopper, S-87-I, 4432/50 gray Bromobutyl rubber compound with B2-04 coating | West |
Secondary Packaging
Secondary Packaging Components | ||||||
Current - Sending Site | Proposed - Receiving Site | |||||
Part No. | Description | Supplier | Part No. | Description | Supplier | Comments |
485690 | Cardboard 25cc nested cells | Not Known. Sourced locally | 20110 | Cardboard shipper (4 trays per shipper) | Not Known. Sourced locally |
Tertiary Packaging
Tertiary Packaging Components | ||||||
Current - Sending Site | Proposed - Receiving Site | |||||
Part No. | Description | Supplier | Part No. | Description | Supplier | Comments |
20110 | Cardboard shipper (4 trays per shipper) | Not Known. Sourced locally | 20110 | Cardboard shipper (4 trays per shipper) | Not Known. Sourced locally | |
N/A | Shipper label | In-house |
Raw Material Specifications for Glycine | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Assay | 98.5%-101.0% | Assay | 98.5%-101.0% | No change |
Identity Infrared Spectrum | Passes Test | Chloride (Cl) | ≤ 0.007% | Necessary changes |
Appearance | Clear colorless solution | Sulphate (SO4) | ≤ 0.0065% | No change |
pH Value (50g/L water) | 5.9-6.4 | Heavy Metals (as Pb) | ≤ 0.001% | Necessary changes |
Chloride (Cl) | ≤ 0.007% | Identity Infrared Spectrum | Passes Test | No change |
Sulphate (SO4) | ≤ 0.0065% | Appearance | Clear colorless solution | Necessary changes |
Heavy Metals (as Pb) | ≤ 0.001% | pH Value (50g/L water) | 5.9-6.4 | Necessary changes |
Hydrolyzable substances | Passes test | Chloride (Cl) | ≤ 0.007% | Necessary changes |
Ninhydrin-positive substances | ≤ 0.5% | Loss on Drying (105oC, 2h) | ≤ 0.2% | No change |
Residual Solvents (EP) (MEOH) | ≤ 0.3% | Sulfated Ash (600oC) | ≤ 0.1% | Necessary changes |
Organic Volatile impurities (USP) | Conforms | Bacterial Endotoxins | ≤ 3.0 I.U./g | Necessary changes |
Loss on Drying (105oC, 2h) | ≤ 0.2% | Ninhydrin-positive substances | ≤ 0.5% | Necessary changes |
Sulfated Ash (600oC) | ≤ 0.1% | Residual Solvents (EP) (MEOH) | ≤ 0.3% | No change |
Bacterial Endotoxins | ≤ 3.0 I.U./g | Organic Volatile impurities (USP) | Conforms | Necessary changes |
Raw Material Specifications for Mannitol | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Assay (HPLC calc on dried substance) | 98.0 – 101.5% | Specific Rotation: α 20/D; 8%, borate complex, calc on dried substance α 25/D; 1% molybdate complex, calc on dried substance | Necessary changes | |
Identity (IR Spectrum) | Passes test | Specific Rotation: α 20/D; 8%, borate complex, calc on dried substance α 25/D; 1% molybdate complex, calc on dried substance | Necessary changes | |
Appearance of solution (20% water) | Passes test | Specific Rotation: α 20/D; 8%, borate complex, calc on dried substance α 25/D; 1% molybdate complex, calc on dried substance | Necessary changes | |
Acidity or alkalinity | Passes test | Related Substances (HPLC) Isomaltitol Unknown impurities, single Sum of related Substances | ≤ 2.0% ≤ 2.0% ≤ 2.0% | No change |
Melting Range Beginning end | ≥164oC 165.5-169.0oC | Sorbitol Maltitol | ≤ 0.1% ≤ 2.0% | Necessary changes |
Specific Rotation: α 20/D; 8%, borate complex, calc on dried substance α 25/D; 1% molybdate complex, calc on dried substance | +23 o - +25 o +137o - +145 o | No change | ||
Conductivity (25 oC) (20% water) | ≤20µS.cm-1 | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | Necessary changes |
Chloride (Cl) | ≤0.005% | Loss on drying (105 oC) | ≤ 0.30% | Necessary changes |
Sulphate (SO4) | ≤0.010% | Residual Solvents | Excluded by manufacturing process | Necessary changes |
Heavy Metals (as Pb) | ≤0.0001% | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | Necessary changes |
Related Substances (HPLC) Sorbitol Maltitol Isomaltitol Unknown impurities, single Sum of related Substances | ≤ 2.0% ≤ 2.0% ≤ 2.0% ≤ 0.1% ≤ 2.0% | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | No change |
Reducing Sugars (as glucose) | ≤ 0.05% | Loss on drying (105 oC) | ≤ 0.30% | No change |
Reducing Sugars after hydrolysis/ total sugar (as glucose) | ≤ 0.4% | Residual Solvents | Excluded by manufacturing process | No change |
Sulphated Ash | ≤ 0.10% | Colony count Aerobic bacteria Yeasts and moulds | ≤ 500CFU/g ≤ 500 CFU/g | Necessary changes |
Water | ≤ 0.5% | Excluded by manufacturing process | Necessary changes | |
Loss on drying (105 oC) | ≤ 0.30% | Passes test | Necessary changes | |
Residual Solvents | Excluded by manufacturing process | ≤ 500CFU/g ≤ 500 CFU/g | No change | |
Microbiological test | Passes test | No change | ||
Colony count Aerobic bacteria Yeasts and moulds | ≤ 500CFU/g ≤ 500 CFU/g | Microbiological test | Passes test | No change |
Salmonella species | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | ≤ 500CFU/g ≤ 500 CFU/g | No change |
E.Coli | In 1g of substance not detectable | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | No change |
Staphylococcus aureus | In 1g of substance not detectable | Microbiological test | Passes test | No change |
Pseudomonas aeruginosa | In 1g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | ≤ 500CFU/g ≤ 500 CFU/g | No change |
Endotoxins (kinetic turbidimetric test) | ≤ 1.1.U./g | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | No change |
Raw Material Specifications for Sodium Phosphate, Dibasic | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Assay (Acidimetric, calculated on dried substance) | 98.0%-100.5% | |||
Identity | Passes test | Identity | Passes test | No change |
Appearance of Solution | Passes Test | Appearance of Solution | Passes Test | No change |
In water Insoluble Matter (Calculated on Dried Substance) | ≤0.20% | In water Insoluble Matter | ≤0.20% | No change |
Sodium Dihydrogen Phosphate | ≤1.7% | Colony count Aerobic bacteria Yeasts and moulds | ≤ 500CFU/g ≤ 500 CFU/g | No change |
pH-value(1%,water) | 8.7-9.3 | In 10g of substance not detectable | Colony count Aerobic bacteria Yeasts and moulds | No change |
Chloride (Cl) | ≤ 0.02% | Sodium Dihydrogen Phosphate | ≤1.7% | No change |
Fluoride (F) | ≤ 0.001% | Sodium Dihydrogen Phosphate | ≤1.7% | No change |
Sulphate (SO4) | ≤ 0.05% | pH-value(1%,water) | 8.7-9.3 | No change |
Heavy Metals (as Pb) | ≤ 0.001% | Cd (Cadium) | ≤ 0.0001% | No change |
As (Arsenic) | ≤ 0.0002% | Fe (iron) | ≤ 0.002% | No change |
Cd (Cadium) | ≤ 0.0001% | Hg (Mercury) | ≤ 0.0001% | No change |
Fe (iron) | ≤ 0.002% | Pb (lead) | ≤ 0.0004% | No change |
Hg (Mercury) | ≤ 0.0001% | Fluoride (F) | ≤ 0.001% | No change |
Pb (lead) | ≤ 0.0004% | Sulphate (SO4) | ≤ 0.05% | No change |
Residual Solvents (Ph. Eur./ICH) | Excluded by production process | Heavy Metals (as Pb) | ≤ 0.001% | No change |
Substances reducing potassium permanganate | Passes test | As (Arsenic) | ≤ 0.0002% | No change |
Loss on Drying (130oC) | ≤ 1.0% | Cd (Cadium) | ≤ 0.0001% | No change |
Particle Size | About 99% | Sulphate (SO4) | ≤ 0.05% | No change |
Raw Material Specifications for Sodium Phosphate, Monobasic | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Appearance | White crystals or granules | Aluminum, calcium, and related elements | Passes Test | No change |
Identification A (Na) Identification B (PO4) | Passes Test Passes Test | Organic Volatile Impurities | Conforms to USP/NF | No change |
pH (1 in 20) | 4.1-4.5 | Identification A Identification B Identification C Identification D | Passes test Passes test Passes test Passes test | No change |
Chloride | Max 0.014% | Clarity and Colour | Passes test | No change |
Sulfate | Max 0.15% | Acidity (pH) | 4.2-4.5 | No change |
Arsenic | Max 8ppm | Chloride (Cl) | Max 200ppm | No change |
Heavy Metals (as Pb) | Max 0.002% | Sulphate (SO4) | Max 300ppm | No change |
Water | 10.0 – 15.0% | Arsenic | Max 2ppm | No change |
Assay (anhydrous based) | 98.0 – 103.0% | Reducing Substances | Passes test | No change |
Insoluble Substances | Max 0.2% | Appearance | White crystals or granules | No change |
Aluminum, calcium, and related elements | Passes Test | Identification A (Na) Identification B (PO4) | Passes Test Passes Test | No change |
Organic Volatile Impurities | Conforms to USP/NF | pH (1 in 20) | 4.1-4.5 | No change |
Identification A Identification B Identification C Identification D | Passes test Passes test Passes test Passes test | Chloride | Max 0.014% | No change |
Clarity and Colour | Passes test | Sulfate | Max 0.15% | No change |
Acidity (pH) | 4.2-4.5 | Arsenic | Max 8ppm | No change |
Chloride (Cl) | Max 200ppm | Heavy Metals (as Pb) | Max 0.002% | No change |
Sulphate (SO4) | Max 300ppm | Water | 10.0 – 15.0% | No change |
Arsenic | Max 2ppm | Assay (anhydrous based) | 98.0 – 103.0% | No change |
Reducing Substances | Passes test | Sulphate (SO4) | Max 300ppm | No change |
Heavy Metals (as Pb) | Max 10ppm | Clarity and Colour | Passes test | No change |
Iron (Fe) | Max 10ppm | Acidity (pH) | 4.2-4.5 | No change |
Loss on drying | 11.5 – 14.5% | Chloride (Cl) | Max 200ppm | No change |
Assay (anhydrous basis) | 98.0 – 100.5% | Sulphate (SO4) | Max 300ppm | No change |
Endotoxin | 2.5 max | Arsenic | Max 2ppm | No change |
Reducing Substances | Passes test |
Raw Material Specifications for Water for Injection | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Description/ Characters | Clear, colourless liquid (USP) | Acid or Alkali | No blue colour develops | No change |
Nitrates | Maximum 0.2ppm (EP) | Nitrogen from Nitrate | No pale red colour develops (JP) | Change needed |
Heavy Metals | Maximum 0.1ppm (EP) | No change | ||
Acid or Alkali | No blue colour develops | Chloride | Not more than 0.05 mg/L (JP) | Change needed |
Chloride | No colour change with Silver nitrate TS (JP) | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | No change |
Sulphate | No colour change with Barium chloride TS (JP) | Residue on evaporation | The weight of the residue is not more than 1.0mg (JP) | Change needed |
Nitrogen from Nitrate | No yellow colour develops (JP) | Total Organic Carbon1 | Maximum 500ppb (USP/EP) | Change needed |
Nitrogen from Nitrate | No pale red colour develops (JP) | Sulphate | No colour change with Barium chloride TS (JP) | Change needed |
Ammonium | Not more than 0.05 mg/L (JP) | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | No change |
Heavy Metals | No colour change develops with Sodium Sulphide TS (JP) | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | Change needed |
Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | Ammonium | Not more than 0.05 mg/L (JP) | Change needed |
Residue on evaporation | The weight of the residue is not more than 1.0mg (JP) | Heavy Metals | No colour change develops with Sodium Sulphide TS (JP) | Change needed |
Total Organic Carbon1 | Maximum 500ppb (USP/EP) | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | Change needed |
Conductivity1 | Maximum 2.1µScm-1 (USP Stage 2/EP) | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | No change |
Total Aerobic Microbial Count1 | Maximum 10 cfu/100ml (USP/EP) | Chloride | No colour change with Silver nitrate TS (JP) | Change needed |
Bacterial Endotoxins1 | Maximum 0.0125 EU/ml | Potassium Permanganate Red. Substances | The red colour does not disappear (JP) | No change |
Raw Material Specifications for Nitrogen | ||||
Current - Sending Site | Proposed - Receiving Site | Rationale for Change | ||
Test | Specification | Test | Specification | |
Description | Colourless inert gas that does not support combustion | Description | Colourless inert gas that does not support combustion | No change |
Identification | Conforms to NF/Ph.Eur/JP | Water Vapour | Colourless humid gas | No change |
Carbon Dioxide | Not more than 300ppm (PH.Eur) | Water Vapour | Colourless humid gas | No change |
Carbon Monoxide | Not more than 5ppm (Ph.Eur) Not more than 0.001% (USP-NF) | Carbon Dioxide | Not more than 300ppm (PH.Eur) | Necessary changes |
Water Vapour | Not more than 67ppm (Ph.Eur) | Description | Not more than 67ppm (Ph.Eur) | Change needed |
Assay: | Not less than 99.5%(Ph.Eur) Not less than 99.0% (USP-NF) Not less than 99.5% (JP) | Carbon Dioxide | Not more than 300ppm (PH.Eur) | No change |
Oxygen | Not more than 1.0% (USP-NF) | Carbon Dioxide | Not more than 300ppm (PH.Eur) | Change needed |
Carbon Dioxide | Any turbidity produced does not exceed that produced by the control solution (JP) | Identification | Not more than 300ppm (PH.Eur) | Necessary changes |
Conclusion:
In the light of the above study, it can be concluded that this study intends to deal with the essential errands that underlies the sending of PH-123 DS from ABC Pharmaceuticals to Phantom Pharmaceuticals. In this regard, the nuances of the flow of the transfer process have been elaborated. Moreover, in order to serve the enquiry of sub-projects, a comprehensive temperature study coupled with a mixing study has been conduct in order to reflect on the imperative temperature and mixing criteria. At the end of the study, a transfer validation protocol has been attempted to devise while considering the analyzed gaps and assessed risks in the introductory phase of the study.
