Active Pharmaceutical Ingredients (APIs) Roundtable

• Albemarle Corporation
• AMRI
• Moravek
• Pfizer CentreOne
• Ajinomoto Bio-Pharma Services

What are some of the current critical issues facing the pharmaceutical industry in regards API sourcing?

Dave Andrews, Director of Sales, US, Ajinomoto Bio-Pharma Services: The pharma industry is facing multiple challenges when it comes to API sourcing. The ability for CDMOs to meet API demand is definitely one of them. Capacity is not always immediately available when needed, impacting planning cycles and increasing the necessity for pharma companies to share their needs 12 to 14 months out with their CDMOs.

Another critical issue is the impact from the Chinese government’s enforcement of laws and regulations relating to safety and the environment. Many chemical producers have been forced to close permanently causing supply chain issues for RSM and intermediates.

There is also a continuing trend of pharma companies to reduce the number of suppliers they work with and therefore looking to build trusted, closer relationships with their suppliers. CDMOs who continuously demonstrate excellence in compliance, on time/in full deliveries, and cost competitiveness, but also introduce competitive new technologies and engage on corporate social responsibility are some of the key attributes required.

Finally, time to market continues to be a critical factor for the pharma industry. CDMOs offering agility, flexibility, end-to-end services (both early and late stage, and perhaps Drug Substance and Drug Product services) are critical to the supply and launch their APIs.

James J. Springer, R&D Manager and Steve Halpin, Analytical Services Manager, Albermarle:

• It is essential that a CDMO has both the appropriate set of assets to provide the full scale of manufacturing capabilities to make PI through PIII and commercial production volumes and has the technical expertise to provide the support for process development and analytical method development.
• Securing a reliable source of advanced Regulatory Starting Materials (RSM) that can also provide volumes and quality throughout the progression of the API from early clinical development through commercial production. Having control over the quality aspects of the RSM and being able to respond to changes in the purity requirements that may come from various regulatory authorities.

Teresa Pallotta, VP, API Sales & Marketing, AMRI: Some of thecritical issues facing the pharmaceutical industry, in regards to API sourcing, include:

• Increased scrutiny by the FDA on Indian and Chinese suppliers. Most of AMRI’s assets are manufactured in the EU and United States, meeting the rigorous expectations of relevant regulatory agencies.
• Lack of reliable supplies, mainly on key intermediates, and increased requirements by regulatory authorities which control early stage API manufacturing under GMP. Providers have to seek options to mitigate supply chain risks.
• Particularly in the U.S. generics market, fierce price competition is leading to product loss/rationalization and therefore, lack of meaningful profitability. This, in turn, can lead to product shortages within the market.
• Capacity constraints to support growing CDMO needs among Western vendors can be challenging.

Paul Moravek, Chief Executive Officer, Moravek, Inc: A trend is emerging in Europe and the U.S. to conduct Phase 0, I and II clinical trials with materials prepared under appropriate manufacturing quality guidelines, such as ICH Q7, to protect the health of the study participants. Carbon-14 labeled APIs are routinely utilized in AME studies. According to Moravek’s understanding, due to the shifting and increased regulatory requirements for quality, there has recently been insufficient capacity for manufacturing of cGMP [14C] APIs, which has resulted in an increased rate of study scheduling delays for early phase clinical trials.

Nicole Strauss, Pfizer CentreOne Pipeline and Innovation Lead: Pharma’s innovators face a number of key issues sourcing APIs to support their overall drug strategies. Perhaps one of the most critical is understanding the regulatory environment in the context of commercial API development and manufacture. Ensuring that custom APIs can meet the different regulatory requirements across the globe is vital, particularly considering increasing product complexity and the additional regulatory considerations that this brings.

Hand-in-hand with regulatory knowledge and experience is scientific expertise – having the experts on the project team that understand what is required to go from clinical scale to commercial production is a vital element to project success.

The embedded CDMO model (self-contained organizations that work within larger companies), offers drug developers access to both the regulatory and scientific expertise of its parent company. With this comes the foresight needed to effectively anticipate and overcome the hurdles a compound or molecule might encounter. An embedded CDMO’s experience (in many cases decades long) will likely provide lessons learned from scaling complex compounds to meet commercial targets and best practices managing the CMC filings and data global regulators demand.

Can you tell us about some new API technical services or manufacturing technologies that can help pharmaceutical companies bring new products to market?

Eric De Vos, Vice President of Global Innovation and Director of R&D, Europe, Ajinomoto Bio-Pharma Services: Continuous flow manufacturing is currently seen as the biggest change of manufacturing technology and an area of great interest and potential for the pharma industry when it comes to scalability, safety and cost of goods. We have introduced flow chemistry at one of our Belgium sites and developed a safe and efficient hazardous chemistry process enabling the very large scale production of a key intermediate.

Scale up of oligonucleotides is an interesting challenge. Current solid phase processes can be costly and present various limitations. In the ADC space, site-specific conjugation has been introduced to produce homogenous ADCs with well-characterized DARs and desired cytotoxicity. Our unique technologies AJIPHASE® (for large scale oligonucleotide manufacturing) and AJICAP™ (site specific ADC coupling) are addressing some of the most critical challenges faced by the industry in these markets.

Many new chemistry technologies for APIs are starting to see more use and acceptance, such as immobilization of (bio-)catalysts and new applications for biocatalysts, as well as the resurrection of older technologies, like photochemistry. Additionally, synthetic biology/ metabolic engineering is on the verge of breakthrough, which would allow for manufacture of more complex building blocks that are similar to compounds that already exist in nature.

Springer and Halpin: ICH Q3D; has forced API manufacturers, to be able to access the elemental impurities in the manufacturing process and the final API. This has required the acquisition of specialized equipment and the development of technical expertise to develop analytical methods to detect and quantitate the individual metals listed in the new guidance. M7 mutagenic impurities; this guidance has also forced the API CDMOs to upgrade the equipment and technical expertise to perform the appropriate evaluations of the API for the presence of potential genotoxic impurities (PGI). This evaluation encompasses synthetic routes of regulatory starting materials along with potential process impurities. Considerable expertise in analytical chemistry along with appropriate capital investment is key to monitoring these trace impurities.

Pallotta: The trend to develop more complex APIs often results in a need to apply several key technologies in the synthesis of a single API, i.e. cryogenic chemistry and hydrogenation or carbonylation and tetracycline chemistry. Therefore, it is crucial that CDMOs offer a variety of these services and technologies for API development.

Some of the services and technologies that have been most helpful as we bring products to market are:

• Continuous flow manufacturing,
• Form manufacturing,
• Biotransformation,
• Fermentation, and
• Capacity for high potency APIs (HPAPIs).

AMRI has teams dedicated to continuous flow manufacturing technologies and a wide range of expertise in biotransformation. With form manufacturing technologies, the ability to back integrate alpha raw materials to mitigate supply chain risks ensures that pharmaceutical companies can work efficiently to develop new products.

Our global capacity for semi-synthesis and enzymatic process development uniquely positions us for fermentation. From early development in the U.S., to scale-up in Spain, and large-scale production in Italy, we support all stages of the process including chemical modification of fermentation products to produce semisynthetic APIs.

HPAPIs represent the new and prevailing way to administer small molecules in lower doses with fewer side effects. AMRI has multiple years of experience and state-of-the-art sites which are able to support our customers’ needs from early-to-late development or commercialization of HPAPIs.

Moravek: Moravek can help pharmaceutical companies bring new products to market utilizing Moravek’s significant capacity to enable timely contract manufacturing of cGMP [14C] APIs. Moravek has made a recent multi-million dollar investment to expand GMP facilities, equipment and staff. For example, Moravek now has four Class 7 cleanrooms and eleven qualified UPLC and HPLC systems ready to support GMP manufacturing. This Southern California company is now one of the most compliant, best staffed and highly equipped CMOs involved in custom synthesis of cGMP [14C] APIs in North America.

Strauss: The chemistries involved in making many small molecule drugs is advancing rapidly as pharmacologists seek more efficient synthesis pathways to manufacture their compounds at scale. One methodology offering great potential is using biology to shortcut organic synthesis. Compounds that once required complex, multistep and sometimes volatile organic chemistries, to manufacture can be made more efficiently and safely through the use of microorganisms and enzymes

Using bacteria or yeast to create chemical intermediates, when feasible, offers a reliable short cut and an alternative to the long, multiple-step chemistries formerly done through organic synthesis. It’s becoming clear that combined chemistries can provide a more cost-efficient way to manufacture today’s complex small-molecule compounds.

When it comes to advancements in processes and technologies, API contractors are also focusing on continuously improving the performance and sustainability of their processes. This includes instituting the 12 green chemistry principles to produce APIs in commercial volumes using fewer resources upfront and preventing harmful waste or by-products from entering the environment in the first place.

When a pharmaceutical company is choosing a supplier for API research/development/manufacturing, what questions should they ask? What qualities and expertise should an API manufacturer/service provider have to ensure that their client gets the best quality product?

Andrews and De Vos: Some of the questions that should be discussed with a CDMO to better understand their abilities and expertise, increase the success rate of the program, and ultimately result in a good match with core competencies and expectations being met include:

• Does the CDMO have financial stability, supply reliability, strong quality systems and compliance, up-to-date facilities, and social, safety and environmental awareness programs?
• Does the CDMO have the capacity to produce the amount of API in the time needed?
• Does the CDMO have a variety of scale-up and manufacturing set ups to allow agility versus changing customer process requirements?
• Can your current R&D or manufacturing process be scaled-up to commercial?
• Does the CDMO offer a strong range of technical capabilities or chemistries to help scale up your product?
• Are you willing to explore, along with the CDMO, new and innovative routes to manufacture APIs (continuous flow, biocatalysis, etc.)?
• Are there special analytical methods that need to be developed in house or by the CDMO?
• Does the CDMO have the right people and experience in place at all levels to manufacture or scale up your API?
• Does the CDMO’s project management and communication style match your needs?

Springer and Halpin:

• How many modern or recent NCE filings have they successfully supported?
• What is the size and talent level in the CDMO process research group and analytical methods development group?
• What types of specialized analytical equipment does the CDMO possess in-house for method development and method validations?
• How does the CDMO go about investigating a process problem at both the early stages of a drug clinical life cycle (PI and PII) and at PIII and validation?
• Tenure of staff and retention of technologist
• What does a typical project team look like, and how much access does the sponsor have to the technologists?

Pallotta:

• Reliability of supply and long-term sustainability are crucial factors when choosing a supplier for API development. Focusing too much on obtaining a low price is a common mistake as an attractive price upfront will not guarantee longterm viability of a product.
• Pharmaceutical companies should ask about a manufacturer’s past experiences. How many products have been developed in the past? Ask them to share their experiences with similar projects. Past experiences matter.
• Look for an organization with a strong project management team, which is key in product development.
• API developers/manufacturers’ resources and assets should be flexible and agile to support your products even as developmental needs change and timelines tighten. AMRI has multiple sites with R&D teams who are able to quickly respond and address changing needs as they come up.
• Large pharma and small biotech companies require different levels of support. Make sure that your provider can accommodate different types of customers with varying needs.
• Does your provider have the capacity to handle everything from early stage development to commercial manufacturing? Look for a vendor who can support you throughout the whole life cycle.

Moravek: A few good questions to ask include:

• How many years of experience in manufacturing of cGMP [14C] APIs does the manufacturer have?
• Have 100% of the manufacturer’s cGMP [14C] APIs and supporting documentation been found to be appropriate for use in clinical trials when evaluated by regulatory bodies in the U.S. and E.U.?
• What is the manufacturer’s capacity? (Timing is often a crucial criteria when selecting a CMO. Some CMOs with limited staffing and/or facilities may delay manufacturing for months or longer.)

The qualities and expertise that an API manufacturer should have to ensure that their client gets the best quality product include sufficient staff (production, purification, Quality Control and Quality Assurance) with experience in handling hundreds of GMP campaigns, sufficient facilities/equipment for timely manufacturing and a perfect track record with submission of cGMP [14C] API for use in the U.S. and E.U.

Strauss: At the top of the list of qualities an API manufacturer or service provider should possess is reliability. This means being reliable in terms of experience and capabilities in quality and compliance, as well as having excellent project management and collaboration practices in place within the company.

Seeing a robust project management system at a CDMO that is a separate entity from its science and technology lines is a telling indicator of reliability and a clear signal that will give any drug developer the confidence that his or her custom API or drug product can be delivered on time.

In line with this, it’s important to pay close attention to a service provider’s quality credentials. What is their inspection history? What are the quality systems that they have in place? Customers measure quality by evaluating deliverables, change control/deviation systems and the overall philosophy of the company.

Underpinning all operational activity should be a positive, can do culture based on transparency and collaboration. A high performance culture is key to a successful CDMO and in a crowded marketplace, it can be the feature that differentiates one strategic outsourcing partner from another.

How has the globalization of the pharmaceutical industry affected API development and manufacturing? How do you ensure that APIs meet differing regulations across the globe?

Springer and Halpin:

• The only way a CDMO can ensure they are capable of meeting worldwide filing expectations is through experience. Having experience of the demand’s multiple filings of a NCE is critical to understanding what aspects of process development and analytical method validations needed to satisfying the various agencies, ensuring sponsors are prepared for the expectations of worldwide regulators.
• Throughout the process development evolution, it is important to develop adequate controls on the RSMs including rigorous analytical method development allowing for expedited method validations if required by particular agencies.
• As sponsors have their scheduled meetings with various regulators, prompt communication is essential between the CDMO and the sponsor to ensure the expectations and timelines of regulators can be met. The foundation of this communication is close communication with all team members from the onset of a project. This ensures that when regulators insist upon changes in specification, or additional analytical method validations, the sponsors and the CDMO can respond in concert to ensure shorter times to NCE approval.

Pallotta: Globalization is expected to improve standards on a worldwide basis, aligning requirements and making drugs safer for all.

We ensure that our APIs meet the differing regulations across the globe via strong, delocalized regulatory teams, who are closely integrated to the agencies and markets. Our teams are in continuous contact with their customers, and are able to quickly respond to regulatory changes without compromising a product’s compliance to the highest of GMP and HSE standards.

Moravek: Recently there have been changes in regulatory quality requirements for APIs to be utilized in early phase clinical trials. Increased quality requirements appear to have been initially driven by regulators in the E.U. who observed some specific issues related to use of [14C] APIs produced without proper consideration for quality.

Moravek adheres to the guidelines of ICH Q7, which have been adopted by numerous regulatory bodies throughout the world, in order to ensure that Moravek’s cGMP [14C] APIs meet differing international regulatory acceptance criteria. Moravek has established manufacturing facilities, quality control procedures and documentation systems in support of production of over 200 cGMP [14C] APIs. 100% of the submitted cGMP [14C] APIs have met U.S. and E.U. quality requirements at this time of heightened regulatory concern regarding quality of APIs for use in early phase clinical trials.

Strauss: In the custom API market, experience with different markets and regulatory environments, plus having people who have “been there before” is sure to help guide the customer’s global regulatory strategy to a better place when it comes to pursuing their business plans. Many embedded CDMOs offer this regulatory expertise through their many years of experience with their own products.

What do you see as the future for API development and manufacturing?

Andrews and De Vos: We see the need for CDMOs to become more agile and flexible to meet the pharma industry needs and expectations. One area that we are seeing agility being highly important is the increased speed from initial discovery to commercialization. We are seeing this cycle time shrink, taking about half as long as it did just a few years previously. Another area for agility is the shift from manufacturing large volume APIs to smaller volume APIs, as there is a stronger focus on APIs for highly defined targets (e.g. rare diseases) that don’t need large volumes.

Agility and flexibility in manufacturing processes is another area, with the shift towards green chemistry and sustainable processes for API development and manufacturing. This will lead to pharma relying more on CDMOs to develop best manufacturing methods and analytics.

Lastly, we expect to see changes to in-line analytical methodology and unit operations to avoid material exposure during sampling and sample transfers to manufacturing and analytical personnel. This is especially important as the in structural complexity and toxicity of the APIs increase.

Springer and Halpin:

• More emphasis on analytical method validations and analytical control.
• More control of regulatory starting materials, with regards to understanding the impact of any change in the process for the manufacture of an RSM. More rigorous analytical testing on the RSM to ensure quality is being retained.
• More focus on potential genotoxic impurities and how they are controlled in the manufacturing process.
• Continuous processing where applicable to the manufacture of APIs and the accompanying PAT.
• Increasing variability in global regulatory agencies approach to filing approvals and appropriate levels of process control.

Pallotta: In the future, I think we’ll see an increase in the outsourcing of CMO services.

There aren't many API providers who can support the whole life cycle of a product – everything from drug development to manufacturing. There are even fewer providers with operational excellence programs to ensure customers are receiving a high quality product at an affordable price.

It will become increasingly important that API providers have the means to fulfill the critical service requests asked of them in-house. This will lead to better integration in terms of capabilities and technical resources.

Moravek: There appears to be regulatory pressure to increase quality of all APIs manufactured for human use, even those intended for use in early phase clinical trials. Based on this trend, it is Moravek’s expectation that cGMP [14C] APIs for use in early phase clinical trials will be required to meet increasing regulatory expectations for quality in compliance with cGMP.

Strauss: API development and manufacturing has always strived for simplifying, shortening timelines, and making more efficient utilization of chemicals, equipment and facilities. Today, advanced biological tools are enabling the use of microorganisms and enzymes to replace multiple chemistry steps thus making API manufacturing safer, greener, more efficient, and less costly. Advanced chemical catalysts are decreasing reaction times and reducing catalyst costs. Finally, manufacturers continue to move toward continuous manufacturing processes to increase speed to market, improve the robustness of tech transfer, and reduce capital costs.