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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
    1. Formulation
    2. Sterile filtration
    3. 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 



+137- +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.

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