Speed up your time-to-market, keep development costs under control and smooth the FDA approval and commercial launch process.
Dana Toops, President, Avema Pharma Solutions
Original link: https://www.contractpharma.com/issues/2021-09-01/view_features/choosing-and-managing-a-cdmo/
Pharma and biotech companies are increasingly turning to contract development and manufacturing organizations (CDMOs) as extensions of their development and manufacturing departments to help bring products to market quickly and efficiently. This trend has increased with companies wanting to optimize their own facilities by moving non-core production to partners or by international companies wanting to move production to a U.S. facility to gain a “made in the USA” claim. For these companies, finding the right partner to outsource product development, manufacturing and even packaging, is critical to their success.
Choosing the right CDMO, or contract manufacturing organization (CMO), and managing them effectively, can be tricky. It’s important to find the right company, with the equipment and expertise needed for a specific product, and a CDMO/customer team that can communicate effectively at every stage of the process. Avéma Pharma Solutions is in a unique position because it takes on both roles: Avéma is a full-service CDMO, supporting the development of solid and liquid dose Rx and OTC products from concept through commercialization. But as a division of PL Developments, which manufactures and distributes private label and OTC-type products, we select and manage CMOs—right now there are more than thirty in our portfolio. In this article, we’d like to share our experiences in choosing the right CDMO or CMO and how to manage the relationship to ensure success.
Managing the initial RFQ
One of the best ways to determine whether a company and a contract manufacturer are a good match is through a rigorous RFQ process where every element of a potential project is discussed. When an RFQ is vague, the chance of success decreases significantly, so the RFQ should include as many details as possible about the excipients, drug substances, process flow, the parameters of the product/formulation development and the scope of the regulatory requirements. It should also include a forecast and a competitive assessment to evaluate whether there is a need for the product or whether there are already well-established competitive products that have saturated the market.
One of the biggest reasons for delays—or errors—when bringing a product to market occurs as the result of miscommunication errors, so it’s very important to establish a harmonious working relationship early on. It’s one of the reasons why Avéma has a single portfolio manager take each project from inception through commercialization, as that person is intimately familiar with every aspect of the product development.
Frequent team meetings are essential, whether in person or via video conferencing. Microsoft Teams can be used to create shared project repositories where data can be shared online. During the initial phases of a project, we typically have client meetings once or twice a week; by the time a product is running on pilot manufacturing equipment, calls may be daily and there will be a constant flow of communication going back and forth. On-site meetings are ideal as they allow the customer to inspect the CDMO’s facilities, but in the case of a tech transfer, we send our own team to observe the product being made. Often, nuances that are missed in the RFQ process can be picked up when seen in person. When site visits aren’t possible, we’ve been using live video to fill in the gaps.
What the contract manufacturer needs to know
To help the CDMO or CMO evaluate a potential project, it’s important to share a comprehensive report on the drug substance, active pharmaceutical ingredients (APIs) and excipients, stage of formulation development, method development and validation, cleaning verification methods, tech transfer and packaging.
CDMOs have different material handling capabilities, so they need to understand if the drug will involve a controlled substance, hormone, small molecule or biological. This will help determine if there is any special handling required. One of the first things Avéma does with a new project is evaluate the molecule in the drug to make sure it's a fit for our facility. We look at the API from the perspective of safety and make sure the handling requirements are within our comfort zone.
The RFQ specifies who will source drug substances, excipients and packaging components. If there are existing suppliers, the CDMO can work with them—in that case a drug master file is very helpful—or help find new sources. Often customers can take advantage of the long-standing relationships already in place with a CDMO. If a vendor has been qualified by the CMO, it can potentially eliminate the need for qualification by the customer. Conversely, every time part of the process is outsourced, it introduces the possibility of delays or additional costs.
In the case of a CBE 30, the products are typically being manufactured somewhere else, so will involve transfer from another site. In those situations, it’s important that the CDMO/CMO determines if existing methods are standard, unique to this product or need to be developed and validated. If they are already in place, the CDMO needs to be able to replicate the tests that are being conducted through a transfer process.
Market launch considerations are also important. We always evaluate products against market conditions to make sure there is a demand for a new drug or another competitor. We project commercial volumes by strength count for the first three to five years and discuss the scalability of the output. We need to make sure we have the right size equipment to handle the product as it scales up.
What the customer should look for
When evaluating a contract manufacturing supplier, the client should look for a company with the expertise and equipment necessary to manufacture their drug with high quality, on-time and full delivery. This involves reviewing the equipment at the facility, speaking to the team members, discussing their expectations on batch sizes and delivery dates, and reviewing the contract manufacturer’s history of success. As a company that sells into major U.S. retail markets, the ability to meet commitments on time is very important to us and we look for a CMO with the same commitment.
For the development of a new drug, the FDA expects quality is built into the product and process using Quality by Design (QbD) techniques. This approach can accelerate the process because it creates a better understanding of the process capability, reduces product variability and defects, and leads to a “right first time,” low defect supply.
The early stages of formulation development typically take the longest as the target formulation needs to be defined, then placebo studies must be performed during method development to assure that the excipients do not interfere with the analytical peaks of interest. The target formulation also needs to be in place to identify critical quality attributes, for the product to move to process design. Process qualification is another step that is time intensive as the process needs to be more intensely evaluated during validation.
During the formulation and process development, the CDMO will review the analytical methods, drug substance specifications and drug product specs. Since many CMOs don’t have a large range of analytical equipment, they might need to outsource some of the testing which can add cost and/or delays to the timeline. Avéma has a full analytical lab precisely because it enables us to control the schedule more tightly. If there’s a situation where we don’t have the analytical equipment required, we consider investment in that equipment if it supports both the customer’s needs and our long-term business goals.
To bring a drug from development to commercialization, our experience shows that starting with small scale pilot manufacturing, and producing small batches with short turnaround times, allows for more characterization of the process using design of experiment (DoE), to support the FDA's QbD expectations. The FDA wants manufacturers to understand the process on a small scale and assimilate those learnings before moving to commercial scale equipment. Every product and every process is different, so each one needs to be individually assessed. Gaining that knowledge and understanding on a smaller scale is quicker and less expensive. At Avéma, all our pilot manufacturing equipment has the same operating principles as our commercial equipment so that it can be scaled up more easily.
Packaging is also a consideration. You should choose a CDMO with contract packaging capabilities for the primary package (bottle or blister) and secondary package if any, or develop a plan to package internally or at another partner’s facility. Depending on the product, there may be bulk hold time limitations specifying the time you have to put the API into the finished dosage form, or the finished dosage form into the primary package. The product may also require special storage and shipping conditions.
Serialization has also become an integral part of manufacturing and packaging Rx products and is required by the Drug Supply Chain Security Act (DSCSA). If the CDMO has serialization capabilities on site, the product can go right into the client’s distribution.
Tech transfer vs. turnkey?
For virtual pharma companies, or for companies developing a new drug, a full turnkey solution with a CDMO taking the project from concept to commercialization may prove to be the most cost effective and efficient approach.
In this situation, the CDMO handles everything from sourcing all ingredients used in the drug product through packaging and serialization of the product. This means the customer can take advantage of the CDMO’s established business and quality systems. Vendor qualification, for example, can be streamlined for APIs, excipients and packaging components. An experienced CDMO also brings QbD experience to the table. This leads to increased product development and manufacturing efficiencies and can result in a robust formulation and process resulting in right first-time performance.
Regulatory strategy
NDAs, ANDAs, CBE-30 and 505B2 products each have different requirements and timelines. While this may sound basic, some of the smaller, or virtual, companies that we work with, may not fully understand the requirements. Working with a CDMO that has experience with FDA submissions and which uses QbD and DoE techniques, can help reduce FDA review times by identifying critical quality attributes, developing a robust formulation and establishing a process design centered around those attributes. We recommend initially using small batches and short turnaround times to minimize FDA information requests and enable a faster approval cycle.
If a company has already developed their product and is looking to move production to another manufacturer, then the two parties would need to execute a tech transfer process. If the product is immediate release, and the equipment at the transferring and receiving facility is “like for like,” then the parties can probably secure FDA approval with a CBE30. If the product has a modified release profile, or if the equipment at the two facilities are different, then FDA approval may require a Prior Approval Supplement.
Minimizing risk
The customer’s biggest concern when working with a contract manufacturer is to minimize the risk for their product. They need a CDMO partner they can trust, with an experienced team, strong quality systems and a proven track record of successfully supplying their customers on time and on budget.
One of the primary techniques we use to minimize customer risk is running small batches first, using the full-scale pilot batch capabilities in an R&D center. Avéma uses pilot equipment that are scaled down versions of our commercial production equipment, which is like for like, with the same types of compression equipment and coding equipment. The pilot scale batches give a true characterization of the process to design experiments, to support the FDA’s mandate, identify any intrinsic products with the product, and allows us to fix those before scaling up. Pilot scale production is faster and more cost effective than doing demonstration batches on commercial equipment.
Small batches are particularly helpful when the company is developing a unique, small molecule NDA product. These APIs are scarce and valuable, so at the early stage of development it doesn’t make sense to move into commercial scale until you have a full understanding of the production process on a small scale.
The process can be defined as part of the QbD techniques, and it helps to streamline a successful scale up to a clinical or pilot scale batch. The ability to validate, to develop a product on small-scale production equipment without having to use commercial production equipment to do the development work reduces both time and cost. Using small scale equipment with identical specifications to commercial equipment eliminates delays and makes sure nothing is lost during the scale-up.
What can go wrong?
Incomplete information, not enough detail about the drug substance or testing requirements can lead to increasing the costs or adding time delays. For example, a client may want to use a third-party for lab work because they are experienced with them—or because it’s a unique method. Unfortunately, bringing in a third party can cause delays because of scheduling conflicts at the lab.
Change in material sourcing can also introduce delays or cost increases. In one recent CBE 30 project, the client’s API was no longer available from the original source so another supplier had to be found. This means it's no longer a clean CBE 30 and must now be processed as a prior approval inspection (PAS).
During development, the CDMO might also discover that a product is not dissolving correctly or not going into a suspension correctly.
In cases where there are challenges with the methods themselves the CDMO might need to redefine or improve those methods to make them work better on equipment or improve the product characterization.
There may be problems with the stability methods, development method or method transfer problems. Methods aren't always robust for transfer and sometime require modifications. If it's a new product, this may take time to get these elements nailed down so that the process being used to manufacture a specific product is adequate for the task.
In one recent project, we encountered an issue with impurities. When we ran the analytical method we saw a peak that looked like it was partially correlating with another impurity peak. This revealed that the method was not sufficiently robust to separate the impurities. In this case we were able to work with the customer to improve the method and solve their problem and eliminate future risks. If the drug had been scaled up to commercial scale with a method that wasn’t robust, it could have led to stability issues down the line.
In it for the long term
There is a tremendous amount of time invested on both sides of the drug development process when choosing a CDMO—and in agreeing to produce a product. On both sides of the partnership, Avéma looks for long-term relationships that can be continued over many years and often over many products. Once a site is approved and audited, there is an inherent advantage to continuing to work together so it’s important to select a contract manufacturer that has the capability to support a product over the long term. If it isn’t a good fit, sometimes it’s better to say no. In fact, Avéma has turned away customers who came back several years later with a project that was a better fit because we were honest up front about our capabilities.
