INTRODUCTION
The process of introducing new pharmaceutical products is evolving. Novel therapies are becoming more complex, global supply chains are increasingly uncertain, competition is intensifying, regulatory scrutiny is more stringent, and timelines are tighter. As a result, pharmaceutical companies must adopt innovative approaches to ensure product safety and quality while maintaining swift market entry. Furthermore, significant trends like the shift towards personalized medicine and the emergence of artificial intelligence are transforming the industry, necessitating greater customization and adaptability for companies to stay competitive.
In the pharmaceutical industry – partly as a response to the issues just mentioned – APIs with strong biological effects are becoming increasingly widespread. High Potency Active Pharmaceutical Ingredients (HPAPIs) are sought after because they provide highly targeted treatments at lower doses, which leads to fewer side effects. They are versatile and are used in drugs for various conditions such as cancer, asthma, diabetes, and autoimmune disorders, etc.
No surprise, the market for highly Active Pharmaceutical Ingredients (APIs) has been growing for a long time. The global HPAPIs market size is estimated being USD 27.19 billion in 2023, and is projected to reach around USD 62.39 billion by 2033 (1).
As the molecular weight and complexity of APIs have increased over time, the importance of biological APIs has also surged significantly. These trends are clearly expected to continue, reflecting ongoing advancements and demands in the pharmaceutical industry.
There are some different classes of highly potent active substances. Without going into details, it is worth to mention the most important groups (the list is not exhaustive).
- Cytotoxic molecules, oncological APIs (both synthetic and biotechnological)
Oncology is a major driver for the HPAPI development. The demand for targeted cancer therapies and personalized medicine is increasing. According to the forecast of MarketsandMarkets, the global precision medicine market was estimated to be worth USD 29.1 billion in 2023 and is poised to reach USD 50.2 billion by 2028, in terms of revenue (2).
This fact is necessitating the development of more potent compounds that can deliver efficacy at lower doses. These compounds exhibit different toxicities, although they are all very potent and thus very toxic. - Synthetic, semi-synthetic, natural hormones
Hormones are chemicals that coordinate different functions in living organisms by carrying chemical messengers. The most well-know group, steroid hormones belong to lipid-derived hormones, further types are the amino-acid derived (e.g. epinephrine, norepinephrine) and the peptide hormones (e.g. oxytocin).
A few hormone molecules may already be able to transfer a given message, thus not a surprise that a very low dose already has significant biological impact. However the dose that causes adverse effects differ significantly among them (several orders of magnitude). - Other synthetic small molecules
It is an extremely diverse group. The reason why it is mentioned is because although many of the synthetic small molecules are not extremely potent, it can be misleading to think that all of them are harmless (for instance, dronates are very toxic). Actually, hazard is the inherent nature of chemicals. - Biological molecules
It is a large group of potent APIs containing eg. antibodies, immune factors, antibiotics, etc. The common feature of these active substances is that they are all produced by a living organism. We cannot go on without mentioning Antibody Drug Conjugates (ADCs), which are a class of biopharmaceutical drugs designed for targeted therapy for treating cancer.
HUMAN FACTOR
We cannot overestimate the importance of human talent and persistence in problem-solving, as well as in implementation, in general. The expansion of the human factor in the development of high-potency API development hinges on leveraging specialized teams with demonstrated track records in this niche area. These teams continuously undergo regular training to stay abreast of the latest technical and technological trends. Additionally, they meticulously follow regulatory changes to ensure compliance and maintain high standards of safety and efficacy in their development/ production processes.
OUTSOURCED ACTIVITIES AND CONTRACT ORGANIZATIONS
As the number of highly potent molecules under development increases, so does the demand for outsourced HPAPI solution providers (Contract Development and Manufacturing Organizations, CDMOs). This is especially true for emerging start-up and spin-off companies, which are usually formed to carry out the development project of a given product or product group.
These virtual companies continue to perform development tasks in the form of services, even with several organizations separately, if it is more cost-effective for them.
In the evolving pharmaceutical landscape, CDMOs must deliver business value.
Advanced materials, access to cutting-edge technologies, innovative manufacturing processes, which are chosen based on critical data-driven insights, now are at stake for pharmaceutical companies. Consulting experts must be committed to creating a collaborative environment where unique challenges are met with customized, forward-looking solutions.
In the management of service providers, the importance of Quality matters is often underestimated, in the mistaken belief that it is enough if the service provider has a functioning Quality Unit. However, ensuring the adequacy of development-related data is the responsibility of the sponsor of a clinical trial, and later, of the Marketing Authorisation Holder (MAH), and not of the service providers, therefore the selection and supervision of the service partner’s activities and appropriate change control processes are extremely important.
TECHNOLOGICAL ADVANCEMENTS
Following technological advancements is crucial in the pharmaceutical industry for enhancing drug development efficiency, ensuring the creation of safer and more effective medications, despite the challenges involved. Staying updated with the latest technologies also allows pharmaceutical companies to maintain a competitive edge and comply with evolving regulatory standards.
A similar key issue is tracking changes and variations during development and technology transfer.
CONTAINMENT AND HANDLING TECHNOLOGIES
One reason that increases the demand for outsourced services is the high cost of entry and specialised equipment. Pharmaceutical manufacturers are expected to adopt a multi-layered approach to containment, in which, if elimination or substitution of a particular chemical hazard is not feasible, engineering solutions play a crucial role (see Figure 2).
A robust containment strategy can be shaped by combining deep toxicological expertise with wide engineering knowledge, ensuring comprehensive protection and safety in pharmaceutical operations. The technical solutions of the isolation already allow as strict as single-digit nanogram (per cubic meter of air) containment performance that is the state-of-the-art.
A contrary requirement is that the facility should also be flexible enough to be able to develop/produce as many different products as possible and to satisfy as many different needs as possible. Thus, engineers have to find solutions for complex situations.
CLEANING AND THE RISK OF CROSS CONTAMINATION
Regulatory bodies, like the FDA and EMA, are imposing stricter guidelines to ensure the safe production and handling of HPAPIs. Compliance with these regulations is a major focus for pharmaceutical companies.
One topic that has seen significant regulatory change over the past decade has been equipment cleaning. The cost of cleaning includes the labour-intensive cleaning process, combined with the cost of materials and verification procedures.
While previously the effectiveness of equipment cleaning was adequately managed by controlling the amount of residue on the contact surfaces of the equipment (4), with the spread of effective drugs, the need for scientific evidence of health-based exposure limits and cleaning limits arose. The increasing number of strong active ingredients and technical development allow the manufacturer to ensure the safety of their product by a combination of other measures instead of the high cost of dedicated facilities.
In 2014, the European Medicines Agency issued new guidance on Health-Based Exposure Limits (HBELs) (5), which requires a science-based analysis to determine exposure limits for patients resulting from cross-contamination.
Cleaning limit values can no longer be determined in the “traditional” way (see (4)), but a toxicologist must evaluate each individual active substance to determine the limit value. The introduction of the HBEL-based cross-contamination risk analysis (5) placed a heavy burden on the industrial players, but it made possible to introduce responsible management of compounds corresponding to the actual effect of the APIs. Before implementing any solution, a risk assessment should be carried out to assess the adequacy of the solution to be implemented (eg. cleaning, single-use system, partial dedication, etc.) and ensure that it meets all process needs.
The ISPE RiskMaPP document (6) outlines that surface ‘retention’ or product residue is very common and it is a risk of cross-contamination. Moreover, the data collected show that surfaces are never completely clean and drug residues remain regardless of diligence. Thus, cleaning remains a focus issue for inspections.
OCCUPATIONAL HEALTH
The main activities of occupational health in pharma include ensuring workplace safety through hazard identification and risk assessment, implementing exposure control measures, conducting regular monitoring of chemicals and health screenings, and ensuring compliance with health and safety regulations to protect workers from potential occupational hazards.
EMERGING TRENDS IN ENVIRONMENTAL SAFETY: ENVIRONMENTAL RISK ASSESSMENT AND ECOPHARMACOVIGILANCE
Efforts to make the production of HPAPIs more sustainable by adopting green chemistry principles and reducing the environmental impact of manufacturing processes are growing and are expected to continue to grow. Sustainability has become an important aspect of industrial production, pointing to the responsibility and critical role of manufacturers in maintaining processes, keeping in mind the future consequences of our current operations.
In the case of the chemical industry, due to the inherently toxic nature of chemicals, we need to make additional efforts for environmental sustainability. As the next milestone in this effort, the new revision on Environmental Risk Assessment guideline (7) was issued by the EMA, and it became effective from September 1, 2024. That means it is obligatory to estimate the environmental risks that are posed by the pharmaceuticals.
Ecopharmacovigilance is a new applied discipline focusing on monitoring the environmental footprint of pharmaceuticals, with the aim of safeguarding our ecosystems and promoting a sustainable future. With the development of trace analytical methods, more and more data are available regarding the quantity, distribution and effects of micropollutants in our environment, including drug residues (e.g. (8)) and we are more aware of the impact of these contaminants on the environment.
Figure 1. Containment classification pyramid (3).
Figure 2. Hierarchy of controls.
REFERENCES AND NOTES
- Nova1Advisor: High Potency Active Pharmaceutical Ingredients Market (By Product: Synthetic, Biotech; By Manufacturer Type: In-house, Outsourced; By Drug Type: Innovative, Generic; By Application: Oncology, Hormonal Disorders, Glaucoma, Others) – Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024-2033
https://www.novaoneadvisor.com/report/high-potency-active-pharmaceutical-ingredients-market, last retrieved on Aug 28, 2024. - MarketsandMarkets: Precision Medicine Market by Tipe (Inhibitors, Monoclonal antibodies, Cell & Gen Therapy, Antivirals, Antiretroviral), Indication (Oncology, Rare diseases, Hematology, Infectious), End user (Hospitals & Clinics, Home care) & Region – Global Forecast to 2028
https://www.marketsandmarkets.com/Market-Reports/precision-medicine-market-215185595.html?gad_source=1&gclid=Cj0KCQjwz7C2BhDkARIsAA_SZKasED88-k_leY239VifSnL88utUpTkTbL3c6elNLhY5CIRtyog-OJ0aAkaVEALw_wcB, last retrieved on Aug 28, 2024. - Courtesy of Richard Denk, Skan AG.
- Fourman GL and Mullen MV. Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations. Pharmaceut. Technol. 1993;17(4):54-60.
- EMA: Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, EMA/CHMP/CVMP/SWP/169430/2012, 2014.
- ISPE: Risk-Based Manufacture of Pharmaceutical Products, 2nd Ed., 2017.
- EMA: Guideline on the environmental risk assessment of medicinal products for human use, EMEA/CHMP/SWP/4447/00 Rev. 1., 2024
- Maasz G, et al. Illicit Drugs as a Potential Risk to the Aquatic Environment of a Large Freshwater Lake after a Major Music Festival. Environ. Toxicol. Chem. 2021;40(5): 1491–1498.EMA: European Medicines Agency
ISPE: International Society for Pharmaceutical Engineering
OEB: Occupational Exposure Band
OEL: Occupational Exposure Limit
PDE: Permitted Daily Exposure
ADE: Accepted Daily Exposure
