Why Selection of a Contract Manufacturing Organization (CMO) for HPAPI Development is Necessary? Highly potent active pharmaceutical ingredients (HPAPIs) are the compounds used extensively today for the treatment of respiratory disorders, cancer and hormonal imbalances. The key factors driving the demand for highly potent active pharmaceutical ingredients (HPAPIs) are the rise in the oncology therapeutics market as well as the surge in the need for better medicines for treating Cardiovascular, Central Nervous System, Hormonal, Eye, Infectious, Metabolic and Inflammatory diseases. How to Select the Right CMO for Large Scale Production of HPAPIs? Choose a globally recognized CMO that focuses on developing HPAPIs through a state-of-the-art facility better known as global HPAPI CMOs. Companies like Roche & Genentech are known for their best in class processes for CMO selection and management. They identify challenges in managing a potent CMO supply chain and propose best practice guidelines for processing highly potent APIs. Check for the description of processes, scale up conditions and drug load (in the case of DP) which can impact suitability. Highly potent molecules need to be reviewed and evaluated against existing equipment and facility audits before they are placed at the site. Across all three API manufacturing categories, buyers of CMO services iterated that roughly one-quarter (26 percent) of outsourced projects are allocated to strategic partners. Despite expressed interest in forming strategic partnerships, the bulk of projects are still allocated to tactical service providers (37 percent to 40 percent), followed by preferred vendors (34 percent to 37 percent). Interestingly, respondents showed higher levels of interest in forming strategic partnerships with high-potency API and biologics manufacturers than they did with small-molecule manufacturers (36 percent and 35 percent very interested as compared to 25 percent, respectively). There can be some correlation between a buyer’s interest level in a strategic partnership with an API manufacturer or a biological Highly Potent API manufacturer (HPAPI CMO) and the likelihood that a tactical provider would advance from tactical to preferred provider and then strategic partner. Just as a higher percentage of respondents were interested in forming strategic partnerships with high potency and biologics API manufacturers, these types of HPAPI CMOs were more likely to move up the ranks in outsourcing relationships. HPAPI manufacturers (HPAPIs CMOs) had the greatest probability of moving from a tactical provider to a strategic partner, with 81 percent stating it is likely a tactical HPAPI CMO will advance to a preferred provider, and 84 percent stating it is likely a preferred provider of HPAPI will become a strategic partner. As interest levels in forming strategic partnerships varied by the type of API manufacturing outsourced, it makes sense that the fundamental attributes that influence CMO selection varied somewhat as well. The attributes that are quantifiable or measurable in nature, such as geographic location or manufacturing capacity, fall under the umbrella of “hard traits.” These attributes are not easily changed, nor can they be quickly changed in order to win a project. The top three hard traits that sponsors desire in a small molecule API manufacturer are improved quality/regulatory positioning, experience, and timeliness. For HPAPI manufacturers or HPAPI CMOs, experience takes the top position, followed by timeliness and the CMO’s financial stability. Sponsors looking to engage a HPAPI CMO for biologics manufacturing prioritize experience, followed by improved quality/ regulatory positioning and, in third position, timeliness. In the research, respondents are also asked about soft traits that influence CMO choice. Soft traits describe the less quantifiable characteristics that one can’t necessarily provide a set of measures to assess; rather they are the attributes that relay the dynamic of the working relationship. Similar to the hard traits, there is overlap across the group, but slightly different prioritization of qualities. Good communication and an understanding of the customer’s requirements were prioritized in the top three across all three API categories. High-potency and biologics outsourcers placed good communication first and understanding of the customer’s requirements third, whereas small-molecule outsourcers placed understanding of the customer’s requirements first and good communication second. A “willingness to go the extra mile” prioritized in the top-three soft traits for both small-molecule and biologics outsourcers (third and second positions, respectively), while high-potency buyers valued a company’s reputation (ranked second) over willingness to go the extra mile. It is vital that HPAPI-handling systems and equipment are tested and verified to meet the necessary isolation requirements. For example, isolation equipment may be expected to meet a containment capability of less than 1 ?g/m3. The capability of equipment, systems, and procedures to contain and isolate materials under expected operating conditions must be verified in a High Potency lab as a critical component of the overall HPAPI-handling program. This process typically requires the use of both air and surface industrial hygiene sampling methods to confirm proper isolation following a detailed sampling plan. In many cases, sampling and testing methods for products in early preclinical or clinical testing have not been developed. Therefore, surrogate products such as lactose or naproxen sodium, are frequently used to complete the equipment testing. It is believed that a promising pipeline of targeted therapeutic drugs will help the HPAPI market progress in the coming years. HPAPI drugs have minimal side effects and impact targeted areas, thereby helping the patient to recover faster with no lingering after effects. The development of HPAPIs has a key driver in the growth of oncology drugs which have shown the maximum demand in the last few years until 2018. The oncology drugs segment has been the leading segment of the global high potency active pharmaceutical ingredient market. This segment is expected to expand at CAGR of 8.3% during the forecast period. The introduction of innovative drugs is the primary growth driver for the oncology segment. Analysts predict that the patent expiry of blockbuster drugs such as Herceptin, Rituxan, and Humira will pave the way for generic drug manufacturers, thereby making these drugs affordable to a wide number of patients. The branded sector constitutes the major share of this market but the patents of this branded sector are expected to expire in the coming few years that will help HPAPI manufacturers (HPAPI CMOs) to cater to multiple clients by producing the generic version of the ingredients in bulk. The other key factor for rapid growth rate is that the majority of blockbuster drugs are nearing patent expiry ad that puts the US government in a position to promote generic drugs to reduce its medical burden. This leads to insurance companies preferring generic drugs over patented drugs for cost effectiveness, while India and China became the hub of HPAPI development through state of the art facilities (HPAPI CMOs) and demand with maximum DMFs with the US FDA. If you have a Highly Potent API, Check all the Attributes of The HPAPI CMO You Need to Consider Given the risks involved in understanding the Chemistry of highly potent active pharmaceutical ingredients (HPAPIs) --- HPAPI Chemistry --- and that during cross-contamination and containment, it is important to consider manufacturing and handling approaches carefully. In fact, because of the exquisite demands of HPAPI manufacturing and complexities of HPAPI Chemistry, many drug developers select a contract development and manufacturing organization (CDMO) partner to make the substance. The discussion below outlines some of the considerations for HPAPI manufacturing and, when appropriate, HPAPI CDMO selection. Check the Salient Features of HPAPI Manufacturing for Selecting HPAPI CMOs With the significant infrastructure and capital investments required for effective HPAPI manufacturing, it is simply not feasible for many of the small and mid-size companies to make this extensive investment. In the suites alone, a top rated HPAPI CMO makes an investment of at least $7 million per year, including its investment in skilled personnel and procedural development. These levels of investment are not possible or prudent for all HPAPI CMOs. Some of the larger pharmaceutical HPAPI manufacturers have chosen to invest in high-potency manufacturing facilities, but even they often outsource manufacturing in the earlier stages of development when the HPAPI Chemistry complications of different types of molecules are minimized so that before potentially transferring production to their own facilities, they are checked for later development stages or for commercial manufacturing. In this way, high-potency development and manufacturing for big pharma is not unlike other outsourcing models in the industry. The manufacture of HPAPIs presents many challenges; however, given the high toxicity, complications of HPAPI chemistry of these compounds and safety is the first and foremost consideration. Manufacturers must have robust engineering controls, risk assessment and risk management processes in place to ensure a safe work environment and prevent cross-contamination. Pharmaceutical companies that outsource HPAPI development and manufacturing look for a CMO that has a proven track record for both safely and effectively managing projects involving highly potent compounds. Such a record includes not only successful commercial production of HPAPIs, but also an excellent audit history, comprehensive documentation and regulatory records. These present significant barriers to entry both for new competing products and CMO suppliers providing these highly-specialized drugs i. e. small molecules or HPAPIs and delivery device combinations. In terms of future growth, China is expected to be the main driver; however, the USA will remain the largest single market ahead of the EU. Isolated HPAPI containment facilities for both drug substances and drug product development and manufacturing should be made available with the following High Containment considerations: • Isolated Class 100,000 suites designed with the most advanced barrier technology, including sophisticated clean-in-place systems • Engineering controls for product containment in segregated suites with dedicated HEPA filtration systems (inbound and exhaust) and individual egress points • Preclinical and clinical trials supply – from 10g to 10’s of kg • Commercial scale manufacturing from grams to 100’s of kg • Handling of Merck Category 4 compounds • Potent solid dose formulation of batch sizes up to 10kg • Facilities FDA and MHRA inspected • Having significant infrastructure and capital investments required for effective HPAPI manufacturing defines the development capacity of a High Potency API Manufacturing unit which is simply not feasible for many of the small and mid-size companies to make this extensive investment. While considering the best HPAPI containment and manufacturing facility, not only should you check the amounts invested in types of molecules that a particular HPAPI CMO produces, but also the equipment installed for proper handling of highly potency APIs and their complex HPAPI chemistry specifications. Various HPAPI CMOs and CDMOs focus on building a workforce of skilled personnel for proper HPAPI containment and handling. The procedural development involves high levels of investment, which may not be possible for many companies and hence are not considered as prudent in all pharmaceutical development companies. Hence HPAPI manufacturing of such high-potency compounds can be outsourced, in fact some of the larger pharmaceutical companies have chosen to invest in high-potency manufacturing facilities, but even they often outsource manufacturing in the earlier stages of development before potentially transferring production of high potency drug substances to their own facilities in later stages or for commercial manufacturing. In this way, high-potency development and manufacturing for big pharma is not unlike other outsourcing models in the industry. The following is a list of questions to ask when selecting an HPAPI CDMO partner: 1. Does the facility or company have experience with HPAPIs? 2. Does it have robust capabilities to prevent cross-contamination? 3. Are contamination-control approaches engineering-based (technology, facility, equipment) or administrative-based (human-centric processes and procedures)? Engineering-controlled processes are far superior. 4. Is the facility overly reliant on personal protection equipment (PPE) for containment and worker safety? 5. Has the facility been specifically designed for HPAPI manufacturing? 6. Can it do small-scale work and scale the product through the various stages of its lifecycle? 7. Has industrial hygiene data been gathered to ensure the controls are actually performing at the expected levels? 8. Does the facility have robust HPAPI regulatory compliance management and quality system programs? The best HPAPI CDMO is the one that can navigate complexity in HPAPI Chemistry, HPAPI Containment and check potency levels for all types of HPAPI Manufacturing needs. Parenteral manufacturing can be a complicated process. Cytotoxics, Antibody-Drug Conjugates (ADCs), highly potent compounds, biologics, and lyophilized products present many challenges and require specialized understanding and expertise. BioPharma Solutions brings longevity of experience in handling complex sterile manufacturing challenges.