Technology in safe transfer of monoclonal antibody PH

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

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.

Table 2.1

Table 2.2

Secondary Packaging

Tertiary Packaging

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.