Group are over fifty players in the global

Group Project Overview – Regulatory Affairs in Life Science

BTEC 612-90- O-2018/Summer

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Dr. Douglas Taylor
Sai Sri Lekha Gaddam
Dewangi Ajay Kothari
Yi Shan Kuo

EPO-HU is a biopharmaceutical company that manufactures biologic products as drug substances. Our company is currently target on erythropoietin (EPO), also as known as hematopoietin or hemopoietin, is a protein that secreted by the kidneys in response to hypoxia. EPO stimulates formation of red blood cell in the bone marrow. Common causes of EPO level elevation include cellular hypoxia, anemia, and hypoxemia due to chronic kidney or lung disease. EPO therapy is mainly used to treat anemic patients with chronic kidney disease, myelodysplasia and from chemotherapy. Those patients may benefit from erythropoietin stimulating agents and it prevents the need for blood transfusion. EPO can be delivered by IV or injection to promote the production of red blood cells in bone marrow.
Market in Development and Trend
There are five different isoforms of EPO currently available on the market, each with different glycosylation patterns. With varying forms, which can be interchangeable and yet produce similar in vivo effects. There are over fifty players in the global market as regulations and standards may vary form different countries in the development of EPO enhancing drug. Based on the development in biopharmaceuticals, paired with the upward trends in anemic patients and those undergoing dialysis, erythropoietin is projected to grow along with the industry. The global erythropoietin (EPO) drugs market size was valued at USD around 7.4 billion in 2016. Increasing incidence of chronic diseases such as end-stage renal diseases, cancer, and HIV is expected to accelerate demand for EPO-stimulating agents as these diseases may cause anemia. To curb rising incidence of anemia, demand for erythropoietin drugs is expected to increase over the coming years.
Current Production Method
The current method of producing erythropoietin stimulating agent in the industry is performed in the Chinese Hamster Ovary (CHO) cells; followed by steps of separation and purification of EPO protein. The Bradford assay and Enzyme-Linked Immuno-Sorbent Assay (ELISA) are used to quantify and reflect the concentration of the protein.
Erythropoietin Manufacturing
The biopharmaceutical manufacturing process of erythropoietin consists of an upstream process where fermentation, clarification activities are carried out and a downstream process where separation, pegylation and purification of the isolated protein is carried out.
Upstream Process
The cell culture media is prepared in the tanks and then transferred to the bioreactors.
Fermentation: The seed cell cultures and cell culture media are fed to a fermentation bioreactor where a fed-batch operational technique is used for days to weeks for the cells to grow to a high density. This process is carried until the cells expressed the desired protein of interest.
Clarification: In this step the protein of interest is separated from the cells. Depending on whether the protein of interest is expressed intracellularly or extracellularly the separation of the protein and the cells is decided. If protein is expressed intracellularly, the cell will be lysed using mechanical or chemical means and if expressed extracellularly the lysis of cells is not carried and the cells will be simply separated. Centrifugation is carried out to collect the cell debris. The supernatant is screened through a micro-fiber to make sure that the cells are not carried to the downstream process.
Downstream process
The downstream process is mainly focused on the purification of the protein.
Separation: Separation columns are used to separate the protein of interest from other proteins and chemicals present in the media. A series of separation column are used.
PEGylation: To increase the Life time of the rhEPO, the protein is couples with polyethylene glycol(PEG). This optimization process is carried out in a PEG Reactor. This is followed again by separation to separate the optimized protein and the sent for purification.
Purification: The resultant optimized protein is further purified in this step. Ultrafiltration is used to separate the protein from particles larger or smaller than it. Diafiltration is used in conjunction with Ultrafiltration technique to exchange the buffer media that contain the protein.
The total process will produce roughly 19g EPO per batch, in about five days.

All the drugs and biological products manufactured in industries are done in good manufacturing practice approval from regarding authorities. If a product is said to be in desired quality it should complies with the regulations that are made throughout the manufacturing and quality processes. Products are produced under different manufacturing processes but the quality cannot be checked into the products it should obtained from the manufacturing process while manufacturing it. Genuine and authorized or standard procedures may produce quality products. Organization controls the production process for 3 reasons those are
1) Reduce variability
2) Increase efficiency and
3) Ensure safety.
Process control can reduce variability in the end product, which ensures a consistently high-quality product. Manufacturing process has many features in process that includes

1) Procedures: the procedures must be followed in stepwise and definite order.
2) Methods: standard methods and operating procedures must be followed.
3) Equipment and supplies: standard equipment from authorized companies must be used for process development
4) Raw materials: raw materials must be procure from authorized stores have high quality raw materials
5) People – They are numbers of individuals, skills they require, goals, and tasks they perform.
6) Support processes – These include those processes which are necessary for the main processes and include such processes as power generation and distribution, generation of utilities and distribution, testing laboratories etc.,

During the product manufacturing process, there are several quantitative process variables which need to be measured, detected and controlled for the gain of quality products. Process control consists of controlling the key process variables during the manufacturing process of the product. Key process variables are those factors which can vary during the production process and have large effect on critical product characteristics, i.e. those characteristics which best indicate the quality of the product besides having effects on productivity, efficiency and safety of men and equipment etc. There are six process components which affect the quality of the products. These variables are
(i) Raw materials
(ii) Facilities and equipment
(iii) Production process
(iv) Packaging and labeling
(v) Testing laboratories and
(vi) Control procedures.

Process control is a concept which propagates that the quality of the products can be controlled at the targeted value, if these six process components are monitored, regulated and controlled at the desired parameters at different stages during the manufacturing of the products leads to attain of quality products at the end.

The process control has the following steps which need to be followed.
• Identification of the critical product characteristics.
• Develop a process flow chart.
• Detection of key process variables.
• Evaluation of the measurement capabilities.
• Determination of the stability of the critical process parameters.
• Determination of the capability of the processes for the achievement of the product quality.

Continuous monitoring of the processes may lead to production of quality products. Six quality dimensions for the parameters which are to be monitored for the process control. The dimensions are (i) relevance, (ii) accuracy, (iii) timeliness, (iv) Accessibility and clarity, (v) comparability, and (vi) Coherence.

• Product features – Some controls are carried out by evaluating features of the product itself. Product controls are associated with the decision so as to ensure that the product conforms to specifications. Inspection is the major activity which is usually performed at points where the inspection results make it possible to determine where breakdowns may have occurred in the production process.
• Process features – These are main areas where most of the controls are directed and which most directly affect the product features. Some features need control so as to avoid or reduce failures. These control are typically are chosen from previously identified critical factors. Process controls are associated with the decision such as the process is to run or stop.
• Side effect features – These features do not affect the product, but they may create troublesome side effects, such as irritations to employees, unsafe working, threats to the environment etc.
These three types of controls are found at several different stages of the process namely (i) setup / startup, (ii) during operations, including running control, (iii) product control, (iv) Supporting operations control, and (v) facility and equipment control.

Process control has many other beneficial effects for the organization. These include the following.
• Availability of the processes and their long term stability.
• User friendly equipment and devices.
• Unified process documents which are traceable.
• Low maintenance costs.
• Availability of appropriate accuracy.
• Availability of process robustness.
• Availability of standardized interfaces.
• Safe working of the processes.
• Negligible interferences.

The function is of process control is performed by documenting production parameters. In a broader sense, this includes the following in-process controls.
• Measured values obtained from process equipment, e.g. temperatures, pressure, speed etc.
• Measured values obtained by operating personnel e.g. product dimensions etc.
• Product attributes, e.g. weight, hardness, appearance etc.
• Measured values obtained from the room environment, e.g. particle counts etc.
• Tests conducted on the input materials.
• Test conducted following completion of intermediate products.

Regulatory Compliance

Since is Recombinant Erythropoietin is Biotechnological products, it is required to be submitted as a “Biologics License Application (BLA)”. BLA should comply requirement as specified under 21 CFR 600.

Since this is quality assignment, we will be submitting Module 2: Common Technical Document Summaries
We will be submitted following section of E- Common Technical Document (eCTD)
1. Module 2.3 Quality Overall Summary
This includes general introduction to the Recombinant Erythropoietin, including its pharmacologic class, mode of action, and proposed clinical use. The introduction should include proprietary name, nonproprietary name or common name of the drug substance, company name, dosage forms, strengths, route of administration, and proposed indications. This will not exceed one page.
Since Recombinant Erythropoietin is biotechnological product, a description of the desired product and product-related substances and a summary of it general properties, characteristic features, and characterization data (for example, primary and higher order structure and biological activity).
The QOS should summarize the data on potential and actual impurities arising from the synthesis, manufacture, and/or degradation and should summarize the basis for setting the acceptance criteria for individual and total impurities. The QOS should also summarize the impurity levels in batches of the drug substance used in the nonclinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process. The QOS should state how the proposed impurity limits are qualified.
2. Module 3. Quality Information related Recombinant Erythropoietin on Quality should be presented in the structured format described in the guidance M4Q.
MODULE 3: QUALITY SECTION OF THE CTD: This includes detailed description of
– The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. physicochemical and other relevant properties of the Recombinant Erythropoietin
– Manufacturing process represents the applicant’s commitment for the manufacture of the drug substance. Information should be provided to adequately describe the manufacturing process and process controls
– SPECIAL CONSIDERATIONS: Since this is Biotech product, information should be provided on the manufacturing process, which typically starts with vials of the cell bank and includes cell culture, harvests, purification and modification reactions, filling, storage, and shipping conditions.
– An explanation of the batch numbering system, including information regarding any pooling of harvests or intermediates, and batch size or scale should be provided
– Relevant information for each stage, such as population doubling levels, cell concentration, volumes, pH, cultivation times, holding times, and temperature should be included. Critical steps and critical intermediates for which specifications are established (as mentioned in 3.2.S.2.4) should be identified.
– Filling, storage and transportation (shipping) details
– SPECIAL CONSIDERATIONS FOR BIOTECH PRODUCTS::Control of Source and Starting Materials of Biological Origin Summaries of viral safety information for biologically sourced materials should be provided
– Source, history, and generation of the cell substrate
– SPECIAL CONSIDERATIONS FOR BIOTECH PRODUCTS: Cell banking system, characterization, and testing
– Sufficient information should be provided on validation and evaluation studies to demonstrate that the manufacturing process (including reprocessing steps) is suitable for its intended purpose and to substantiate selection of critical process controls (operational parameters and in-process tests) and their limits for critical manufacturing steps
– Cell culture and harvest
– Purification and modification reactions
– Filling, storage and transportation (shipping)
– Control of Source and Starting Materials
– Source, history, and generation of the cell substrate
– Sufficient information on validation and evaluation studies
– Container Closure System
– Stability data and Conclusion

1. Surabattula et al. Research in Biotechnology, 2(3): 58-74, 2011
2. C. Ergie, J. K. Browne, Development and characterization of novel erythropoiesis stimulating protein (NESP), British J. Cancer Res. 84, 3-10(2011)
3. U.S. Department of Health and Human Services, Food and Drug Administraiton, et. al., Guidance for Industry. Biosimilars: Questions and answers regarding implementation of the biologics price competition and innovation act of 2009. (2012)


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