Process Validation of a Biopharmaceutical Product

Process validation of a biopharmaceutical product
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Table of Contents
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Process validation of a biopharmaceutical product  PAGEREF _Toc418159059 \h
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1.0 Mini-project Descriptor Part 1: Sequence of process validation activities  PAGEREF _Toc418159063 \h
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1.1 The necessary process validation workflow  PAGEREF _Toc418159064 \h
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2.0 Mini-project Descriptor Part 2: Process Validation prerequisites  PAGEREF _Toc418159065 \h
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2.1 Planning  PAGEREF _Toc418159066 \h
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2.2 Process Development  PAGEREF _Toc418159067 \h
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2.2.1 The activities that lead up to the formal process validation  PAGEREF _Toc418159068 \h
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2.2.2 Prerequisite for raw materials  PAGEREF _Toc418159069 \h
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2.2.3 Description of the process  PAGEREF _Toc418159070 \h
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2.2 Equipment and Facilities  PAGEREF _Toc418159071 \h
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2.3 Prerequisites regarding training  PAGEREF _Toc418159072 \h
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3.0 Mini-project Descriptor Part 3: Characterization of the cell line  PAGEREF _Toc418159073 \h
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4.0 Mini-project Descriptor Part 4: Study protocols in process validation program  PAGEREF _Toc418159074 \h
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4.1 Viral Clearance  PAGEREF _Toc418159075 \h
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4.2 Impurity Clearance  PAGEREF _Toc418159076 \h
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4.3 Process Consistency (conformance lot validation)  PAGEREF _Toc418159077 \h
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4.4 Process Intermediate Stability  PAGEREF _Toc418159078 \h
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4.5 Process Solution Stability  PAGEREF _Toc418159079 \h
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4.6 Drug Substance fill, freeze, thaw, and storage  PAGEREF _Toc418159080 \h
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4.7 Mixing studies (process and process solutions)  PAGEREF _Toc418159081 \h
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4.8 Chromatography resin and reusable filter membrane lifetime validation  PAGEREF _Toc418159082 \h
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5.0 Mini-project Descriptor Part 5: Viral contamination of medicinal products  PAGEREF _Toc418159083 \h
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5.1 Preventative measures  PAGEREF _Toc418159084 \h
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5.1.1 Screening of viral contamination in the Master Cell Bank  PAGEREF _Toc418159085 \h
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5.1.2 Working Cell Bank  PAGEREF _Toc418159086 \h
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5.1.3 Cells at the limit of in vitro cell age  PAGEREF _Toc418159087 \h
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5.1.4 Tests for retroviruses  PAGEREF _Toc418159088 \h
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5.1.5 In vitro Assays and In vivo Assays  PAGEREF _Toc418159089 \h
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5.1.6 Antibody production tests  PAGEREF _Toc418159090 \h
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6.0 Mini-project Descriptor Part 6: Operational and performance parameters  PAGEREF _Toc418159091 \h
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6.1 Critical Operational Parameter  PAGEREF _Toc418159092 \h
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6.2 Non-critical Operating Parameters  PAGEREF _Toc418159093 \h
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6.2.1 Non-Key Operational Parameters  PAGEREF _Toc418159094 \h
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6.2.2 Key Operational Parameters  PAGEREF _Toc418159095 \h
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6.3 Performance Parameter  PAGEREF _Toc418159096 \h
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7.0 References  PAGEREF _Toc418159097 \h
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Process validation of a biopharmaceutical product
1.0 Mini-project Descriptor Part 1: Sequence of process validation activities
A typical sequence of process validation activities for a pharmaceutical product is shown in the table below:
Table 1: Sequence of process validation activities (Loftus & Nash 2010)
Process Validation Activities1Carry out preliminary clearance of process containments2Commence viral clearance activities 3Carry out more virus clearance activities4Begin process characterization studies (test limits)5Approve the process validation plan6Develop and approve the protocols of process validation7Perform full-scale validation 8Perform small-scale validation such as contaminant clearance and hold times9Develop, approve, and archive reports of process validation10Perform continuous process validation studies11Assess operational parameter range
The sequence of activities commence from development, throughout each of the stages of experimental tests, and to finally full-scale production of the commercial pharmaceutical product. The activities of process validation have complementary supporting activities which take place in parallel (Brady 2013). Prior to commencing clinical phase 1, it is important to carry out preliminary clearance of process contaminants (Seiberling 2009). The process contaminants comprise impurities that are product-related and impurities that are process-related. It is notable that product-related impurities consists of truncated forms, aggregates, and modified forms. Process-related impurities consist of DNA, host cell proteins, media elements, chromatography ligands, serum components, and leachables. It is also necessary to evaluate the removal of adventitious agents for instance bioburden, endotoxin, and viruses (Brady 2013).
According to the Food and Drug Administration, impurity and viral clearance studies during the lifecycle of the product must at all times be carried out following Good Manufacturing Practices circumstances as well as apt scientific principles and methods (Brady 2013). The quality division of the pharmaceutical manufacturer must constantly take part during the impurity clearance studies.
The batch manufacturing can then be initiated for clinical trials use. A clinical process report should be produced initially before the production of batch records. Suitable concepts of Good Manufacturing Practices should be observed with an appropriate means of approval for each one of the batches (Brady 2013). A mixture of calibration, controls, as well as appropriate equipment qualification is thus needed to guarantee excellence of the clinical trials materials. This is also the appropriate time for embarking on formal stability studies (Carlton & Agalloco 2010). It is notable that by this phase, the investigational new drug (IND) application should have been presented to relevant American regulatory bodies, or the organization should have presented an Investigational Medicinal Product report of clinical tests to appropriate bodies in Europe for approval. After approval, the next step is to proceed into clinical trials phase 1 (Brady 2013). Developing the process validation master plan should be started early on during the lifecycle of the medicinal product. The plan has to be sanctioned before the execution of formal qualification studies.
Process characterization studies are initiated in order to categorize operational parameters for instance non-key, key, non-critical, critical, as well as performance features, and establish acceptance ranges as well as test limits (Brady 2013). During this phase, it is important to make sure that the validation master plan is approved totally. The scaled-down models should then be developed and qualified according to the vital pre-approved qualification protocols. Scaled-down models in most cases are utilized to show clearance of contaminants (Food and Drug Association 2011). Every major process parameter has to be maintained at steady levels. For chromatographic apparatus for instance, low rate to bed volume ratio; linear flow rate; pH; column bed height; temperature; contact time; as well as the concentration of protein, salt, and product must be demonstrated to be the same as full-scale, actual commercial manufacturing.
In addition, qualification studies would be carried out according to pre-approved protocols on the following: process solution stability; process intermediate stability; mixing studies – process and product solutions –; drug substance fill, thaw, freeze, and storage; and chromatography resin as well as re-usable filter membrane lifetime validation (Brady 2013). Carlton and Agalloco (2010) reported that in this phase, the operational ranges and parameters should have been defined and their design space determined. After the process definition has been established, the commercial process description can be prepared and the process control strategy defined (Food and Drug Association 2011). From here, the commercial production master batch records can now be written. Assay development and characterization of the protein can then proceed separately. By the conclusion of the second phase of the clinical trials, it will be important to have each of the analytical methods and assays totally qualified and/or validated (International Conference of Harmonization 2012).
This is now the right moment to carry on to clinical trials phase 3 and perform the pivotal clinical studies. It is notable that as clinical trials phase 3 continues, attention can be focused on qualifying the full-scale production facility that would produce the conformance lots. The rest of the process validation protocols are then developed and pre-approved (Brady 2013). Before the clinical trials stage 3 ends, the small-scale contaminant clearance studies protocols should have been completed and post-approved. The protocols for the other independent studies should also have been completed and post-approved (Sofer 2012).
Full-scale validation studies can be performed, which would conclude with the production of the essential conformance lots. These conformance lots are monitored carefully in order to demonstrate processing consistency (Baseman, Long & Mollah 2013). By this time, a lot of the abridged as well as small-scale confirmatory studies at full-scale have all sufficiently shown contaminants clearance. When combined, the whole of the process validation studies now successfully show the capacity of the company to satisfy the preset acceptance criteria for the performance parameters. The process summaries are then developed for summaries (Brady 2013).
The pharmaceutical company can now have its regulatory license application presented in the form of a Marketing Authorization Application (MAA) in Europe or as a Biological License Application (BLA) in America, and then pass a pre-approval inspection. In addition, the company needs to have finished, approved, and stored its different process validation reports (Doo Hyun 2008). The company can proceed into commercial production and distribution after it has gotten regulatory approval. Without delay, it then implements a continuing verification program comprising monitoring reviews as well as associated generation of periodic reports (Brady 2013).
The necessary process validation workflow
Process validation workflow (Brady 2013)




Process
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2.0 Mini-project Descriptor Part 2: Process Validation prerequisites
There are several typical prerequisites to a process validation study. Process validation necessitates that the following are already established with documentation done before process validation studies are performed: qualified production support systems; validated assays as well as standardized instruments; and the process must be developed, characterized, and documented fully in a development report (Close et al. 2014). Process knowledge and total understanding of the technology and equipment to be employed in the process is vital to process validation. In essence, operational/input parameters as well as performance/output parameters must be identified, with apt acceptance criteria or operating limits specified for both parameters. The process characterization studies carried out in scale-up and process development establish the knowledge database of this process (Brady 2013).
It is worth mentioning that for full-scale conformance lots, process validation is normally focused on process performance at the set-point of every operating-parameter range. Given that rationalization of the operating range for every operation might not be expressed during full-scale validation, the ranges have to be substantiated during the development stage with the use of suitable process characterization studies that are commonly performed at lab-scale (Brady 2013). Spiking studies might show impurity removal that calls for a scale-down model study since they cannot be carried out at full, commercial scale (Wong & Chatterjee 2011). The scaled-down models employed during process validation or characterization have to be substantiated as being representative of the full-scale unit operation including showing that the ensuing intermediate or drug substance is the same (International Conference of Harmonization 2012).
2.1 Planning
An effective validation program is one which is started early on during the product lifecycle and is only performed whenever the product or process gets to the end of its lifecycle. An effective process validation usually commences early on during development stage of a pharmaceutical by acquiring preliminary process data as well as facts. Even though formal process validation is unnecessary during Stage One, certain exemptions are made for product safety issues (International Conference of Harmonization 2009). In the commercial development stage, additional comprehensive process information must be gathered which illustrates the key as well as crucial operational parameters; product impurity profile; standard, highest, and lowest operating ranges; and performance parameters as a function of every individual unit process and operation all together. In essence, this information has to be acquired in a sequence of process characterization dossiers and/or development dossiers (Levine 2009).
2.2 Process Development
Process validation is a process that is actually evolving (Jain & Kumar 2011). It is the process in which process understanding is increasingly built up in the development stage and goes on during the commercial stage of the lifecycle of the product (Bhambure, Kumar & Rathore 2011).
2.2.1 The activities that lead up to the formal process validation
With every incremental change during the different phases of process optimization and scale-up, it is critical to have a general awareness of the capacity to validate the process. The activities that lead up to the formal process validation are as follows: host cell system/cell line selection; molecule selection; harvest process development; cell culture or fermentation process development; purification process development; formulation development and product presentation; and analytical method development. Other activities include identification and development of every filtration system; pharmacokinetic/toxicology studies; process characterization; and process scale-up (Hyuk Jae 2008).
2.2.2 Prerequisite for raw materials
Vendors must be chosen and specifications have to be determined, particularly for materials of non-compendial-grade; that is, non-pharmacopoeia (Brady 2013).
2.2.3 Description of the process
The process description specifies every process step and details the process operational as well as performance parameters linked to every step (Food and Drug Association 2010).
2.2 Equipment and Facilities
For Good Manufacturing Practices, facilities, utilities, and equipment must undergo qualification before process validation. Cleaning validation has to be carried out at the same time as process validation. Selection and appropriateness of cleaning agents for processing aid surfaces such as chromatography resins or product-contact surfaces should be determined before initiation of processing validation (Carlton & Agalloco 2010). A documented assessment has to be carried out so as to make certain that the apparatus is apt for its intended usage. The assessment has to include apparatus operating capacity, safety, and capability, in addition to a review of every process-wetted component for durability, compatibility, as well as possible leachable substances. Additionally, programs for preventive maintenance, change control, and instrument calibration should be established (International Conference of Harmonization 2009).
2.3 Prerequisites regarding training
Contractors or staff members who are involved with the execution or preparation of validation protocols need to have the suitable training, education, and experience to carry out the allocated tasks, and this needs to be documented (Witcher 2013).
3.0 Mini-project Descriptor Part 3: Characterization of the cell line
Cell lines are understood as sorts of cell populations that originate through sequential subculture of primary cell populations that could be banked. The different kinds of cell lines include continuous cell line; host cells; and diploid cell lines (Barker, Posner & Griffin 2013). Biotechnology drug substances are obtained from cellular sources which are capable of influencing consistency of the production process as well as quality of the drug substance. For instance, if the genetic construct or cell line is not stable, variability in the quantities of impurities such as nucleic acids, host protein, in addition to other biological elements might arise (Ho 2011). The process of purification might lack the capacity to inactivate or get rid of adventitious agents such as mammalian virus. As such, complete characterization of the starting cellular materials is needed to understand and control the result of the manufacturing process. Production cell lines are usually qualified during the production of the working cell bank and master cell bank so as to ensure safety of the products throughout clinical development (Brady 2011; Jatto & Okhamafe 2012). Studies need to show the efficacy of the manufacturing process in removing adventitious agents and controlling cell-derived impurities with the use of small-scale models of the manufacturing process which reflect the amplification of working cell bank cells and master cell bank cells.
4.0 Mini-project Descriptor Part 4: Study protocols in process validation program
4.1 Viral Clearance
Owing to the source of some biological products utilized in the production of drug substance – that is, serum additives, human cell, and/or animal cells – there is a likelihood that the components and/or cells employed in cell culture might be contaminated with viruses of humans or animals (Haider 2011). Certain processes of manufacturing, for instance mammalian, have to be designed in order to accomplish inactivation or removal of viruses which can be present – endogenous to a cell line – and to inactivate or eliminate possibly non-detectable adventitious viral contaminants – exogenous. Moreover, facilities and processes must reduce the potential introduction of adventitious agents throughout the process (Food and Drug Association 2010).
In biopharmaceutical processes, the expectation for viral clearance is that at least 2 robust complimentary or parallel viral clearance steps have to be validated in a biopharmaceutical process of manufacturing in which viral contamination might be a concern. The following steps are able to clear viruses: detergent/solvent treatment for enveloped viruses, low pH, affinity, size, heat, as well as ion exchange chromatography (Griffin 2009). Retrovirus clearance studies might be needed by the regulatory authorities before trials of phase 1. In essence, viral clearance studies for a complete panel of model viruses are required to support product registration filings and might as well be required before pivotal or phase – trials. The viruses that are utilized in clearance studies must be chosen basing upon the kind of cell line, the history of the cell line, and exposure to additives and media which might possibly have viruses (Barker, Posner & Griffin 2013).
4.2 Impurity Clearance
Clearance of impurity is assessed using laboratory-scale studies as well as testing of in-process pools from conformance lots. Dickson (2014) stated that impurity clearance is done in order to remove impurities which can negatively affect safety of product or intended biological activity to adequately low levels. The first scientific assessment must be carried out to recognize and choose those impurities that require study. Representative impurities are picked basing upon the possible safety concerns or as representative of a class of impurities (Douette & Bolon 2013). It is important that the risk assessment considers biological activity, quantity, toxicity, and closeness of the impurity to the drug substance; that is, where during the process the impurity is found. Impurities can be divided into 2 groups: (i) product-related impurities such as aggregates; modified forms like isomerized, altered conjugated, deamidated, oxidized, or disulfide-linked forms; and truncated forms. (ii) Process-related impurities such as downstream-derived; cell culture-derived; and cell substrate-derived (Brady 2013, Douette & Bolon 2013). Clearances studies could be utilized in removing the necessity for establishing lot-to-lot testing such as lot release specifications for the aforementioned impurities.
4.3 Process Consistency (conformance lot validation)
Showing consistency basically confirms that developmental expectations for process performance and control are satisfied and that the manufacturing plant, procedures, and equipment are able to consistently manufacture a drug substance which satisfies specifications as well as product quality characteristics (Sahoo, Choudhury & Manchikanti 2009). It is notable that consistent performance parameters, for instance yields of drug substance with suitable product quality characteristics throughout manufacturing, actually exhibit process consistency. Demonstrating consistency beyond the first conformance lots may necessitate ongoing monitoring of a subset of the initial parameters assessed during validation. The criteria that is utilized in evaluating consistency must be described in the validation protocol (Vicente et al. 2011). Demonstrating consistent manufacturing usually requires at least 3 consecutive conformance lots. More batches might be needed for intricate processes in order to address issues which crop up during validation or for processes which are not robust (Brady 2013). Conformance lots need to confirm that the process could be run over and over again within the limits specified by the lab-scale characterization studies (Mercier et al. 2014). Conformance lots need to be successive and have to demonstrate that the company’s department of manufacturing can perform the process consistently. A good reason for not incorporating failed lots, though they may not be r...