Patient safety and reliable supply of medications

Patient safety is our guiding value at Orion, and a fundamental priority in everything we do. It is integrated into all of our processes through the value chain, and something on which we do not compromise.

At Orion, we provide patients with products that are effective, safe to use, of high quality, and available for the patients who need them. We ensure patient safety through rigorious management of our operations, upstream and downstream supply chain, and by continuously monitoring any signs of adverse effects or quality issues over the course a product’s lifecycle.

We promote health and quality of life with our products and by sharing guidance to consumers and healthcare professionals on the correct and proper use of the products.

As a pharmaceutical company, we are legally obligated to monitor the safety and quality of our products. We ensure that the drugs developed, manufactured and marketed are proven to be safe for their users, effective for the indications for which they are approved, and consistent with the quality standards set for them.

Ensuring the availability of medications by preventing supply disruptions and by communicating through appropriate channels constitutes part of ensuring patient safety. We also make certain that our suppliers meet the same quality requirements as our own operations.

Orion’s responsibility of it’s product portfolio

Pharmaceuticals constitute a significant global market in which pharmaceutical companies network with each other extensively. One drug product contains four to ten ingredients commonly purchased from highly specialised chemical plants from all over the world.

Orion is responsible for the patient safety of the products that are under it’s marketing authorisation, irrespective of their origin or ingredient origin. Our production operations are located in Finland, but we also procure active pharmaceutical ingredients and final products globally.

We have a broad product portfolio of generic prescription drugs in almost all therapy areas. We develop new treatments for cancer, central nervous system disorders, asthma and chronic obstructive pulmonary disease. Our product portfolio includes biosimilars, self-care products and veterinary products.

Our product portfolio contains products manufactured by other pharmaceutical companies as well as products that we manufacture ourselves but for which other companies deliver active pharmaceutical or other ingredients. Similarly we also produce and export active pharmaceutical ingredients (API) to the global market. For some APIs our global market share can be considered significant, for example the share of methotrexate produced by Fermion has more than 30% market share globally.

Because of the broad product range, risk management of the delivery reliability is crucial. Possible problems related to the delivery reliability or quality of the products of external manufacturers may cause a risk to our supply capacity.

Also, maintaining the required high quality standard means that our production is closely monitored and managed to minimise product quality risks. Authorities and customers undertake regular and detailed inspections and audits of development and manufacturing of drugs at our production sites. Carrying out any corrective actions based on the inspections and audits may, at least temporarily, have effects that decrease delivery reliability.

Good operating practises

The guiding principles of the quality standards of our entire supply chain are based on full compliance with EU-regulated good operating practices in manufacturing, laboratories and R&D. They rely on efficiency and fluency of the processes, product safety, as well as the consistent quality and high supply capability.

Good Practices (GxP) requirements include manufacturing and quality control (GMP), distribution (GDP), pre-clinical (GLP), clinical (GCP) and pharmacovigilance (GVP). As our products are also sold outside the EU, we make sure that our operations are in compliance with the good practices applicable in all those countries as well.

As the manufacturer and the marketing authorisation holder, we are responsible for the quality and safety of our products and for making sure that we follow these good operating practises. At the moment we have 300 employees working in quality assurance to ensure patient and consumer safety in proprietary, generic and self-care products.

The Finnish Medicines Agency Fimea is the authority that inspects pharmaceutical and active pharmaceutical ingredient (API) plants in Finland according to the Pharmaceutical Products Act, and on behalf of the authorities of other EU member states. The Mutual Recognition Agreement between the USA and the EU provides a possibility for the Food and Drug Administration (FDA) in the USA to also rely on inspections performed by Fimea. Moreover, healthcare authorities from many other countries frequently inspect our operations.

Ensuring safety in the beginning of the product lifecycle

We monitor safety throughout each of our products’ lifecycle. Our quality management system ensures that each product batch released for sale is in accordance with marketing authorisation, and we systematically follow the outcomes of quality and safety monitoring. In events that cause concern, we instantly carry out the necessary procedures to ensure patient safety.

The research and development phases are the basis for ensuring quality of a medicinal product or API. The manufacturing methods and equipment as well as the requirements for the raw materials and the products itself are determined during these phases.

Industrialisation is included as an elementary part in the product development phase. The purpose of industrialisation is to make sure that the manufacturing methods are applicable on an industrial production scale and that each production batch corresponds to the product described in the marketing application.

The launch of a new proprietary product in the market is preceded by extensive phased research that delineates the drug's pharmacological properties, such as its efficacy and safety. Clinical trials involving human subjects can only be conducted with the approval of the regulatory drug authorities. The pharmacology and safety of a drug candidate are extensively studied using preclinical laboratory models and by monitoring tolerability and adverse effects throughout the clinical trials.

Our responsibility goes wider than just the products we launch ourselves. We are responsible for all products under our marketing authorisation, whether it is produced in our own production facilities or by a supplier.

We purchase our materials and ready-made products from suppliers whose qualifications we have confirmed. We expect our suppliers to operate in accordance with the Good Practices (GxP) requirements. Audits of their manufacturing sites are important steps in the process of selecting and monitoring our raw material and product suppliers, as well as in ensuring the continued availability and consistent quality of the raw materials and products and the traceability of the documentation. In the qualification process for API suppliers, we also audit the manufacturers of the intermediate materials used in the manufacturing process of the API.

Ensuring quality in our production

Each batch of raw material is sampled, analysed and released for use by our quality organisation before use in production. Packaging materials and the printed packaging information are also checked accordingly. In-process samples are taken during the manufacturing process to ensure the consistent quality of the product. Samples of each manufactured batch are taken and analysed, and the batch documentation is reviewed before it is approved for sale.

In the approval process, we check that the batch has been manufactured in accordance with the marketing authorisations granted for the product by the authorities in different countries and that all the results of the analysis meet the requirements confirmed in the authorisations. When releasing products for sale, we use even stricter internal quality criteria in order to ensure the required quality throughout the entire shelf-life of the product.

With the help of the batch documentation, all the materials and the phases of manufacturing, quality control, transportation and distribution can be traced without gaps. This traceability is important if there is reason to find out if a potential manufacturing deviation from the specification has occurred. We also follow the stability of each product in stability studies through the labelled expiry date of the product.

The quality management procedures for APIs are described in the control strategy. The quality control methods are established at an early stage when the multi-staged manufacturing process is being developed, whereby the purity profile and the corresponding quality requirements for the ingredient are determined. The quality of the API is monitored throughout the manufacturing process, and all batches are analysed before they are released for sale.

Monitoring quality and safety via pharmacovigilance

At Orion, we ensure that our products provide the effective treatment defined in the marketing authorisation. We continuously monitor quality and any adverse events that may arise during the development and the use phase of the drug. If any such event comes to our attention, we make immediate investigations and corrective actions accordingly.

We work to ensure the safety of our products throughout their lifecycles. We aim to ensure that the benefits of using a medicinal product significantly outweigh any possible risks or adverse impacts related to the use of the product. We maintain a pharmacovigilance system, which is required by legislation, and regulatory requirements in order to monitor the safety of our medicines and to implement timely and effective risk mitigation actions when appropriate, to ensure patient safety.

All customer complaints concerning our products are assessed, and the root causes are investigated. We handle complaints via a centralised process, which enables us to efficiently monitor complaints throughout the entire lifecycle of a product. This also facilitates the monitoring of the impacts of corrective and preventive actions.

Pharmacovigilance operations

Our duty is to monitor the safety of our medicinal products throughout their lifecycles, right from the early phases of R&D up until the product is no longer available on the market. This is done via pharmacovigilance, the science and practice of monitoring the effects of medicinal products after they have been licensed for use, especially in order to identify, evaluate and prevent previously unreported adverse reactions.

Several functions of our company are involved in the pharmacovigilance processes coordinated by the Global Drug Safety organisation situated in our headquarters. Qualified and trained experts are responsible for assessing and carrying out the activities related to managing the benefit-risk balance of the products. Our pharmacovigilance operations and quality management system are compliant with international regulatory requirements and guidelines.

The core activities in the pharmacovigilance operations also include risk management, safety reporting to healthcare authorities, various periodic safety reviews and internal audits of pharmaco¬vigilance activities.

We prepare a Risk Management Plan (RMP) for all new medicines, which describes what is known and not known about the medicine’s safety and states what measures will be taken to prevent or minimise its risks. The authorities approve the RMP, and the measures agreed in the RMP are implemented when the product is placed on the market. The measures are product-specific and can include, among other things, additional materials or educational programmes for healthcare professionals to ensure the safe and correct use of the product. RMP is maintained throughout the lifecycle of the product.

All data concerning the safety of our products is collected into a centralised assessment, and continuously monitored and reported. Information is collected from various sources throughout the product lifecycle, such as from clinical trials, spontaneous reports and feedback from healthcare professionals, literature, regulatory authorities and patients regarding any adverse effects, medication errors, interactions or overdoses.

We collect product safety information worldwide and report it to the relevant regulatory authorities. Both we and the regulatory authorities evaluate the information to detect safety signals that might affect the benefit-risk balance of the products to identify any emerging safety issues at an early stage. In addition to continuous signal detection procedures, we periodically review the cumulative data. These Periodic Safety Update Reports are prepared and submitted to the regulatory authorities. In the report, all available safety information and the benefit-risk profile of the product are thoroughly evaluated and measures to minimise risks are proposed, if necessary.

We work in close collaboration with authorities in evaluating the safety of our products and on the balance between risks and benefits. When necessary, we take action to ensure patient by, for example, updating the information provided in the summary of product characteristics and the package leaflet, providing information or training to healthcare professionals, adding contraindications, precautions or warnings to the product information, or discontinuing sales. The possible actions are always taken in a controlled manner in collaboration with healthcare authorities.

Since January 2018, customers have also been able to contact the Orion call center and talk about their products with experts at the weekends and outside office hours, and ask about Orion’s products or report any adverse events or make a complaint about products when needed. The call centre is open every day of the year between 08:00 and 22:00. 24/7 reporting is also made possible using easily accessible reporting and contact forms on our web pages, which have been further developed to ensure easy use and to comply with GDPR related requirements.

Audits to ensure operational quality

Manufacturing and sales of medicines and APIs are subject to regulatory permissions. During the authorisation procedure, the regulatory authorities have ensured that Orion has the appropriate qualities for the operations, and that each drug we release meets the specified requirements. The regulatory authorities conduct regular inspections to monitor and assess our research, supply chain and pharmacovigilance operations. In these inspections, they also assess our effectiveness to follow up any adverse effects of our products, our processing of complaints and our readiness to recall a product from the market.

The inspections are conducted in the name of the medicinal authorities of the EU and other countries in the so-called PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Scheme) collaboration, which covers 49 countries. In addition, our operations are regularly monitored and inspected by authorities representing non-PIC/S countries.

We proactively ensure and monitor the adequacy and compliance of our operations and facilities by means of internal control. We carry out systematic audits and management reviews of our operations and continuously develop our internal procedures.

Our customers, partners and contract manufacturing principals also assess our ability to operate in compliance with the regulations and the commitments agreed in the contracts. In their inspections and audits they check the adequacy and regulatory compliance of our supply chain and R&D of pharmaceuticals and APIs. Our customers also conduct sustainability audits to Orion's operations.

Correspondingly, we monitor the adequacy and regulatory compliance of our sub-contractors, suppliers and other collaboration partners. We collect self-assessments and carry out on-site audits to make sure that the external parties involved in our supply chain, R&D and distribution meet the regulatory requirements, such as the Good Manufacturing Practices, and obligations mutually agreed in the collaboration contracts. We also follow up corrective actions and preventive actions for audit observations.

Recalling the product

We closely monitor any signals of eventual quality defects. Medicinal products and APIs that do not comply with their specifications or may cause harm to their users will immediately be recalled from sale and distribution, and from consumption if necessary.

Depending on the seriousness of the case, the product is either recalled from wholesalers and retailers only, or also from patients. We take similar measures if there are deficiencies in the integrity of the data in the manufacturing documentation. The decision to recall a product is made in cooperation with the health authorities.

We have internal processes to ensure immediate initiation of recalls, prompt and accurate communication and efficient processing in such cases. We also regularly test the efficiency of our recall procedures. All of our employees are obliged to inform the local person responsible for pharmacovigilance about any adverse effect events of which they have become aware. In addition, our phone operators forward any queries requiring urgent action to our experts, even outside of office hours.

Medicine information

At Orion, we look after patient safety by sharing accurate and up-to-date information about the use, storage and safety of our products via our own marketing and corporate communication channels. This is done to the extent permitted by law and the commonly adopted industry codes.

Pharmaceutical products may only be sold and used under a product-specific marketing authorisation granted by a pharmaceutical regulatory authority. A summary of product characteristics determines the facts shared with healthcare professionals and included in product-specific package leaflets.

Marketing authorisation is granted and maintained to be valid for products that are safe to use for their indicated purpose, are proven to be therapeutically effective, appropriate for use as drugs, meet quality requirements, and are appropriately manufactured and labelled. The authorisation also defines the product’s indication – i.e. the purposes for which the medicine can be used.

The drug and health authorities maintain national and international drug databases, which contain up-to-date information for every product with a valid marketing authorisation. The information and arguments presented by the manufacturer and/or the marketer in any communication about the product must always fully conform with the registered product information for the valid marketing authorisation.

For the sale of an API, Fermion shall provide its customers with registration materials (DMF, ASMF, CEP) approved by regulatory authorities which form part of the marketing authorisation documentation concerning the medicine in which the API acts. For each batch, the customer shall receive the related supply documents, an analysis certificate and a safety data sheet concerning the substance. All packages are labelled with warning signs and traceable information.

Fighting falsified medicines via serialisation and anti-tampering

Falsified medicines pose a serious challenge globally. They have not been checked for quality, safety or efficacy. They are often disguised as authentic medicines, but may contain ingredients of substandard quality or may come in the wrong dosage. In Europe and Finland, falsified medicines are not currently a significant problem, but preventative actions are being taken proactively.

To prevent the entry of falsified medicinal products into the legal supply chain, the EU Falsified Medicines Directive came into force in February 2019 across Europe. Regulation requires that medicines released for sale after 9 February 2019 contain certain mandatory safety features: the unique identifier (serial number and product code) and an anti-tampering device on the pharmaceutical package. Serialisation requirements are already in force in many countries, for example in China, the USA, South Korea, Saudi Arabia and Turkey.

Serialisation across the European pharmaceutical market means that all individual prescription medicines must be traceable throughout the value chain. In practice, all pharmaceutical packaging must include a unique identifier so that a sales package can be traced all the way back to the production plant and production line. In addition to including a serial number and a product code, prescription medicine packaging is sealed, so that the customer can be sure that the packaging has not been opened.

The EU Directive concerns all prescription medicines for human use; therefore, non-prescription medicinal products and veterinary medication are not under the directive.

Orion has been preparing for the serialisation requirements for several years. All of our packaging lines have been updated in order to comply with the directive, and the entire supply chain has been successfully verified. New serialised products are being manufactured and delivered to pharmacies continuously. We will continue to implement this regulation, and ensure our products comply with it and similar existing and upcoming requirements in other markets.

In addition, Orion aims to take actions against counterfeit products when needed to minimize the threat to public health and help ensure the integrity of Orion products. It is Orion’s goal to understand the needed steps to recognize and avoid counterfeit products. This is done by building a robust trademark portfolio and other protective legal measures.

Avoiding availability challenges

We aim for maintaining a high level of service at all times. In 2019, the availability of Orion’s pharmaceuticals was around 97% in Finland. The service level has been at a competitive level in 2019 compared to other pharma companies, despite the fact that there have been a lot of availability challenges globally.

Such global challenges have been caused by, among other things, the consolidation of API manufacturing capacity. That can lead to certain active pharmaceutical ingredients or excipients to have very few or even only one manufacturer globally. There have also been delays in implementation of serialisation requirements by some of the partners that supply us with finished products.

At Orion, we proactively evaluate potential risks throughout the value chain and take necessary actions in order to mitigate them, in order to secure product availability. One of the key elements of risk management is having close and systematic collaboration with all of our main suppliers. The collaboration aims to mitigate risks and ensure expected service level together with the entire supply chain, and according to commonly agreed targets with suppliers.

We also minimise the risk of capacity shortage in the distribution of medications by ensuring the availability of alternative means of distribution.

Management of patient safety

The management of patient safety concerning pharmaceuticals is arranged as follows:

  • Chief Medical Officer: carries the primary responsibility for the Company’s medical governance and medical ethics.
  • Global Medical Affairs, in collaboration with the Global Commercial Operations: responsible for our compliance with the legal requirements concerning the marketing of pharmaceuticals in all countries where we are present.
  • Qualified Person responsible for pharmacovigilance (QPPV) (in Orion Director, Global Drug Safety): responsible for the establishment and the maintenance of the pharmacovigilance system of the marketing authorisation holder.
  • The Accountable Director (in Orion Vice President, Quality Management): primarily responsible for our medicinal products being manufactured the correct way and that the quality requirements are being met. Qualified Persons in our Quality Assurance organisation: review all data for each product batch before product release and certification to ensure that the batch fullfills all requirements as defined in marketing authorisation and the GMP.
  • The Accountable Director at Fermion: primarily responsible for active pharmaceutical ingredients being manufactured the correct way and that the quality requirements are being met. Active pharmaceutical ingredient batches released for sale by independent Quality Assurance departments at each of Fermion’s production sites.