Abstract
The Biopharmaceutical drug product chosen is Herceptin which contains the active ingredient trastuzumab. Herceptin is an anticancer drug used to treat early stage breast cancer and metastatic gastric cancer when the cancer produces a protein called `HER2` in large quantities on the surface of the tumour cells. The drug will be marketed Europe and will comply with all European Medicine Agency (EMA) guidelines.
GMP Guidelines
In order for the pharmaceutical industry to main a high standards of quality management in the development, manufacture and control of medicinal products once a product is granted its marketing authorisation it must be compliant to all good manufacturing processes throughout the production of the drug. The directives lying down the guidelines and principles of GMP for medicinal products in humans are found in commission directive 2003/94/EC and the GMPs for veterinary medicinal products are found in the commission directive 91/412/EEC. The guide is presented in three parts, Part I covers the GMP principles for manufacturing of medicinal products, Part II covers GMPs for active substances which are used as starting materials in the production of products and Part III which was recently added in 2010 and contains the GMP related documents which clarifies the regulatory expectations of the EMU and is used as a source of information on current best practices.
Five of 9 basic requirements for medicinal products which is found in Part I, that must be GMP compliant to ensure a quality product within the EU are Personnel, Premise and equipment, Production, outsourced activities and self-inspection.
In order for the correct manufacture of medicinal products there must be a sufficient, qualified, competent personnel to carry out detail’s roles. All personnel must fully aware of the principles of GMP that can affect the and must receive initial and continuous training, including hygiene instructions, relevant to the personnel needs which is up to the manufacturer to ensure all these requirements are adhered too which is enclosed in chapter 2 of the Eudralex GMP guidelines. It is required that senior management should appoint a key personnel where the responsibility can be delegated with the head of production which have some responsibilities like to ensure the products produced and stored maintain their required quality, ensure that production records are evaluated, ensure appropriate validations are complete and to delegate work from head of quality control which carry out the responsibilities as to ensure all necessary testing is carried out, to approve or reject any materials along the production process and to approve and monitor contract analysis. Both of the head of production and head of quality control have a responsibility in terms of the key personnel in their department to provide continuous training to the, Training is a big factor required which the manufacturer must carry out training for all personnel whose duties include production, storage areas or control laboratories. The importance of continuous training to maintain practical effectively and avoid any major mistakes. Untrained personnel should not be permitted into the production or quality control areas but when absolutely essential like an inspector or auditor they would be prescribed personal protective equipment (PPE) and closely supervised. Also, personal hygiene is a major guideline that must be followed by all personnel within a business with extensive hygiene should be implements to avoid contamination of the product and to protect the employee. This would include PPE to be worn by employees, a full medical examination upon employment, hand-washing facilities and any sort of unhygienic practices such as eating within production areas are strictly prohibited.
Another area that must be GMP compliant would be the premise and equipment when producing products which is found in chapter 3 of Part I of the Eudralex GMP guidelines. The premise and equipment must be designed to minimise the risk of errors, effective cleaning must be applied to avoid cross contamination of product. In general, between all areas like the production area, storage area, quality control area and ancillary area, firstly all basic hygienic measures should be taken and each area should be separate from each other. The premises should be laid out in a logical order so each stage can be passed onto the next to avoid mix up and just for convenience. Open channels should be avoided where necessary but when necessary should be shallow to facilitate cleaning and disinfection especially in the production area and in storage areas there should be adequate storage conditions like suitable temperature, humidity level etc. according to the product being stored and should be regularly monitored. Any equipment should be regularly cleaned when necessary, certain equipment should be regularly calibrated to ensure accuracy and precision and any sort of pipes supplying supplies should be sanitised to minimise microbial contamination.
Production must also be GMP compliant as shown in chapter 5 of Part I of the Eudralex GMP guidelines. As stated above the main aim is to minimise cross-contamination where every stage of processing should be protected from microbial growth and other causes of contamination and production could be performed by trained personnel which links into chapter 2 the GMP compliant area of personnel. All incoming and finished materials should be physically quarantined until they are released for use or distribution and checks on all incoming materials, processed materials and outgoing products should be preformed to ensure they are of the highest quality and no deviation from the procedure have occurred. All aspects of the production area should be closely monitored from pipes to outgoing product to ensure its of highest standard.
In chapter 7 of Part I of the Eudralex GMP guidelines is outsourced activities. The principle of this is to deal with the responsibilities of manufacturers towards the competent authorities of the member states. Any activity that is outsources should be appropriately defined, agreed and controlled to avoid misunderstanding which could cause low quality products. If any produce or production is required to be outsourced of its usual premises a written contact is required covering any activities and any technical arrangement made in connection to it and should be arranged in accordance to the products marketing authorisation holder. All legalities, risk management principles and GMP must be adhered to and this is a responsibility of the contract giver that the contract receiver is provided with all necessary information relating to the product. The contract receiver must not make any unauthorised changed outside of the contract and must be able to carry out satisfactory work.
The last chapter in Part I of the Eudralex GMP guidelines is self-inspection. Self-inspections should be conducted regularly to monitor the implementations of GMP practices, and any corrective measures should be imposed. These examinations should be at pre-arranged intervals in order to verify the conformity with quality assurance. This chapter briefly links into one of the annexes of personal hygiene in chapter two of personnel (Eudralex,2020).
References
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Who is the EMA?
Figure 1- European Medicine Agency Logo.
The European Medicine Agency (EMA) is the regulatory authority responsible for the scientific evaluation of applications for European marketing authorisation for medicinal products. The EMA is a decentralised agency of the European Union and is governed by an independent management board, it’s a networking organisation whose activities involve thousands of experts from across Europe on a day to day basis.
The European Agency for the Evaluation of Medicinal products (EMEA) was first established in 1995 but later changed its name to the EMA. It has worked across the European union to ensure the best use of scientific resources for the evaluation, supervision and pharmacovigilance of human and veterinary medicines in which it has a 25-year tract record of ensuring safe products. The EMA works with all 27 countries in the EU and the 3 EEA-EFTA states which is Iceland, Liechtenstein and Norway and once a marketing authorisation is granted for a product its valid for all members countries of the EMA. The aim of this establishment was to minimise cost for pharmaceutical companies when wanting to release a drug to the market, instead of applying to each country individually the EMA was set up so companies would only apply to one place and once granted a marketing authorisation it would be valid for all member states, a more convenient and efficient way (centralised procedure). It was also established to harmonise the work of existing national medicine regulatory bodies. The EMA headquarters since it has been found was located in London, UK but since the UKs withdrawal from the EU the headquarters was forced to relocate in Amsterdam in the Netherlands in March 2019. The EMA is constantly updating their guidelines and expanding in line with the new EU legislation, since 2000 the ema has become responsible for products developed in specialised areas such as medicines for rare diseases, herbal medicines, medicines for children and advanced therapy medicines in which it now has six scientific committees composed members from of all EU and EEA-EFTA member states. Since 2012 the EMA opened their doors are took the next step in ensuring quality, safety and efficacy of products with the creation of pharmacovigilance and a risk assessment committee.
Figure 2- EMAs headquarters in The Netherlands.
The EMAs main mission is to foster scientific excellence in the evaluation and the supervision of human and veterinary medicines for the benefit of public and animal health within the European Union cooperating closely with international partners reinforcing EU contribution to a global harmonisation (ema.europa.eu,2020).
About Herceptin and the HER2 gene
Herceptin is a recombinant DNA-derived proetin which contains the active ingredient trastuzumab, which is a cancer immunotherapy drug used to treat 25-30% of primary breast cancers and 6.8-42.6% of advanced gastric stomach cancers in which there is over-expression of the protein human Epidermal growth factor receptor 2 (HER2). The HER2 gene belongs to a family of 4 transmembrane tyrosine kinase receptors. This HER2 gene produces the protein HER2 receptors, the over-expression of this protein causes malignant tumours to form as this protein sends signals to stimulate cell replication resulting in the cell to proliferate uncontrollably (Hao, Yu, Mcbride and Huang, 2019).
Trastuzumab is an immunosuppressant which are used to prevent acute transplant rejection, autoimmune disorders and in this case malignancies. Monoclonal antibodies are a type of immunosuppressant which are lab engineered molecules which are used as a substitute of the bodies naturally producing antibodies that can mimic the immune systems attack on harmful cells. These monoclonal antibodies are harvested from antibodies produced by a single B cell and are very specific, targeting a single type of receptor which is the extracellular domain of the HER2 receptor (Schneble, 2015).
Figure 3- Protein structure of the monoclonal antibody Trastuzumab, the active ingredient in Herceptin.
This murine antibody is a biochemically purified IgG1 immunogloblin which has a molecular weight of 148 kiloDaltons and is composed of 1,328 amino acids.
Figure 4- Chemical Structure of Trastuzumab.
Discovery of Herceptin
In the 1980s the monoclonal antibody against HER2, trastuzumab was developed after it was discovered that HER2 could stimulate extensive growth and division of cells. A team of NCI researchers found that this gene HER2 was found in high levels in breast cancer cells and concluded that this gene has a direct link to the development of cancerous tumours. The hypothesis which was concluded by these researchers was that if HER2 was blocked that breast cancer would be slowed down, which led to the development of a monoclonal antibody to block the proteins function. Researchers in Genentec developed the HER2 specific antibody, trastuzumab. The clinical trials began in 1998 and in 2006 FDA realised it to the American market to be used as a chemotherapy drug (Peddi and Hurvitz, 2013).
Mechanism of Action of Trastuzumab
Trastuzumab binds to the extracellular domain of the HER2 complex (molecular weight of 185,000 daltons) and initiates a complex of intracellular events, as the hyperactivated HER2 protein is causing the cells to divide uncontrollably, it inhibits the HER2 downstream signalling, it also inhibits other pathways that has been activated by HER2 like mitogen-activated protein kinase (MAPK), this pathway promotes cell growth and replication. From blocking the signals from HER2 it is inhibiting the division of the cells and stopping the cell from being able to carry out its metabolic functions leading to cell cycle arrest and suppression of growth in the G1 phase. It also activates the immune cells like killer T cells to come to the tumour site to kill the overexpressed HER2 cells (Vu and Claret, 2012).
Figure 5- Illustration showing the mechanism of action of trastuzumab, trastuzumab is a monoclonal antibody which binds to the extracellular domain of HER2 preventing signalling leading to blockage of other pathways inducing apoptosis.
How to obtain a Marketing Authorisation.
A Marketing Authorisation is the process of reviewing and assessing the evidence to support a human or veterinary medicinal product, once a marketing authorisation of a product is granted the product is allowed to be put on the market to be sold where it is valid for a period of 5 until the product is reassessed. In order to obtain a marketing authorisation a manufacturer must make an application for approval and it must comply with all the requirements of good manufacturing processes (GMPs) as defined in European guidelines and legislation which this is monitored throughout the products production period through regular onsite inspections. If the company fails an inspection the marketing authorisation is removed, and the marketing authorisation holder must cease trading immediately. Within the EMA applications for marketing authorisations are obtained using the centralised procedure. This is when the company submits one single marketing authorisation application and if granted it applies to all member states of the EMA.
When obtaining an EU marketing authorisation, the following procedure is followed:
Figure 7- Steps taken to apply for a Marketing Authoristion.
Prior to submitting an application an eligibility request is needed from 18 to 7 months before submission of a MA application, this is to find out whether a product can be evaluated under the centralised procedure.
Where the company will then submit a pre- MA submission request form about 7 months before applying to notify the agency of the intended submission date.
The Pharmacovigilance Risk Assessment Committee (PRAC) and the committee for medicinal products for human use (CHMP) will then appoint rapporteurs who will lead and conduct the scientific assessment of the product.
In order for applicants to obtain procedural and regulatory advice from the agency it is recommended that the company undergoes a pre-submission meeting, This should happen 6-7 months prior to the MA submission and if the pre-submission meeting is deemed successful the validation process is speed up.
2-3 months prior to the MA submissions the applicant is required to re-confirm the submission date and inform EMA on any cancellations or delays.
The application is then submitted through the online esubmission gateway or web client which is an online platform made up of representatives from the National Component authorities, the EMA and industry on the confirmed date.
The EMA will then undergo a technical validation of the application.
The application will then begin to be assessed and is evaluated by the CHMP with put from the PRAC on all aspects of the risk-management plan and if the application involves advanced-therapy medication the Committee for Advanced Therapies (CAT) will be involved in this process. This can take up to 210 active days for the full scientific evaluation to be complete.
After the evaluation the CHMP will issue a scientific opinion on whether the medicine may be authorised or not, where the EMA sends thee opinion to the European commission which will issue a marketing authorisation.
The European commission will decide on the marketing authorisation within 67 days of receiving the CHMPs opinion. Once granted the centralised marketing authorisation the EU commission will take legally binding action and the product will be valid is all EU member states. The decision is published in the community registrar of medicinal products for human use and the EMA will publish a European public assessment report (EPAR) for each medicine. If refused MA from the commission, the EMA publishes a refusal EPAR with a question and answer and assessment report (ema.europa.eu,2020).
Mode of Administration
Monoclonal antibodies are given subcutaneous, intravenous and are usually used in combination with other chemotherapy drugs.
Herceptin has two routes of administration, it given in an injectable or the traditional way is through an intravenous infusion. The first dose of the IV infusion of Herceptin takes 90 minutes and 30 minutes giving at different doses depending on your weight for about 18 cycles (up to a year). Whereas the subcutaneous injection is given at 600mg and is injected into the thigh, alternating between left and right for each dose and takes about 2-5 minutes every three weeks (Van den Nest, 2019).
Figure 8- Herceptin bottle and its packaging which is used for IV infusion.
Adverse effects, contradictions and precautions of Trastuzumab
Indications-
- Adjuvant breast cancer
- Metastatic breast cancer
- Metastatic gastric cancer
Precautions-
- Cardiac disease
- Drug interactions
Contradictions-
- Hypersensitivity to any component of the protein.
- Neonate
- Autoimmune hepatitis- where he bodies immune system attacks its liver.
Adverse effects-
- Headache, nausea, vomiting and diarrhea
- Altered sense of taste
- Weight loss and hair loss?
- Cold symptoms such as sinus pain, sneezing, sore throat
- Insomnia
- Mouth sores, loss of appetit
Serious side effects-
- Hepatotoxicity- chemical induced acute or chronic liver disease
- Neurotoxicity- chemicals produce an adverse effect on the CNS and PNS
- Cardiomyopathy- weakening of the heart muscles, inhibiting its ability to pump blood around the body.
Drug interactions-
Patients who receive anthracycline after trastuzumab are at an increased risk of cardiac dysfunction. This is because of drugs long washout period as it can take 7 months for it to leave the body (MD, 2000).
Manufacturing process of Monoclonal Antibodies
These humanized antibody's are produced by mammalian cells in particular for Herceptin they are produced in Chinese Hamster ovary cells because of their high protein production. The cells are suspended in a nutrient medium and stored in a bioreactor as seen in figure 6. These cells will then go on to be purified by affinity chromatography and ion exchange and will undergo removal procedures to remove any unwanted debris or contaminants (Herceptin,2012).
Figure 6- Manufacturing process for Monoclonal Antibodies.
Conclusion
Herceptin is a biological monoclonal antibody used as an anti-cancer therapeutic which has a 10-year survival rate of 72.2% to 84%. This drug targets the protein receptor HER2 which its over expression causes various cancers, trastuzumab inhibits the signalling of HER2 and also activates the body’s immune system to destroy these malignancies. This biopharmaceutical drug was approved by the EMA after an in-depth application process of adhering to regulatory authority and then gaining their marketing authorisation which allows the drug to be sold to all member states in the EMA. The marketing authorisation holders must comply with GMPs to maintain their marketing authorisation in order to ensure high levels of effectiveness and have no contamination of the drug.