Drug substance and drug product release specifications have numerous uses throughout the product lifecycle. They guide process development and provide a framework for risk assessment, stability testing, and shelf-life determination. Today’s post provides examples of release specifications for small molecule and for antibody drugs and discusses common issues that arise in specification setting.
Small Molecule Release Specifications
Example specifications for small molecule drug substance and drug product are provided below:
Some common issues to think about in the development and application of these specifications include:
HPLC Assay Development: The heart of any small molecule release specification is the HPLC method, as such it carries the weight of characterization and stability assessment of the API and the drug product. Ensuring that the method is robust and stability predictive is critical. Think about issues like reagent quality early on. As an example, trace impurities in reagents can create unwanted interfering peaks; even reagents marked specifically for HPLC use, must be evaluated to guarantee lack of interference; preferably several lots of each reagent should be trialed.
Sterility: Sterility testing should be free of interference from the active and from excipients. Consider carefully the possibility that the active could suppress growth as the sterility testing is planned and executed.
Stability: Consider carefully the drug substance and drug product storage conditions. Ideally, a long shelf life will be achieved—during early clinical work, the number of manufacturing campaigns will be small, leading to a drug product supply crisis if the drug product has a shorter real time shelf life than predicted.
Antibody Release Specifications
Example specifications for antibody drug substance and drug product are provided below:
Some common issues to think about in the development and application of these specifications include:
pH: Seemingly a simple issue, pH can be a vexing problem. As protein solutions are concentrated during UF/DF operations, the pH of the final solution can deviate from the diafiltration buffer. Great care should be taken to ensure that the drug substance starts out in the center of the specified pH range to prevent the product from drifting out of acceptance over time.
Stability Data: For a biologic, 6 months of real-time stability is required for the IND; this contrasts with small molecule drugs. For that reason, early development stability studies are even more critical in order to de-risk the stability testing and shelf-life condition selection for the initial GMP lot. Negotiate the timeline for stability testing prior to signing any contract with your CMO/analytical testing laboratory to ensure that there are no painful surprises.
Biosimilarity: Biosimilarity is a complex concept; additional characterization beyond the assays listed in the release specifications is required to fully understand product comparability.
Evolution of the Specification: As additional manufacturing experience is obtained, the characterization space of the drug will be more fully understood. By analyzing and trending manufacturing data, the specification can be tightened in order to more accurately express what is acceptable and non-acceptable drug substance and drug product.
Complex Mechanisms: Biological molecules have even more complex interactions with the body than small molecules. Make sure that you understand how your molecule performs in the clinic through relatively cheaper and lower risk early trials before pushing all the companies chips onto the table in a Phase 3 trial. Many companies have failed to recover from a badly planned Phase 3 trial.
Conclusions
Careful thought and collaboration applied to drafting the release specifications allows the entire project team to focus attention on the important properties of a drug. As living documents, they are revised throughout the product lifecycle to incorporate new manufacturing knowledge about the drug. Through this process, these documents become tools in assessing risk, planning stability studies, and claiming shelf life.
Disclaimer: This post is reprinted from PharmaTopoTM. This post is reprinted from PharmaTopoTM. PharmaTopoTM provides commentary on topics related to drugs. The content on this website does not constitute technical, medical, legal, or financial advice. Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.
The Convention on Pharmaceutical Ingredients (CPhI) was just held in Frankfurt. As the self-described “leading networking event for pharmaceutical industry,” the CPhI events are great places to meet and learn about contract manufacturing organizations (CMOs) [1].
Today’s post is about selecting and working with a contract manufacturer. To simplify the discussion, let’s assume that the goal is to select a small molecule active pharmaceutical ingredient (API) manufacturer, but similar considerations apply to drug product and labeling and packaging manufacturers.
Contract Manufacturers
Pharmaceutical contract manufacturers are like Uber and Airbnb, they allow your company to use an asset which you do not own. Through contract manufacturing organizations, there are massive possible savings to a startup pharmaceutical company on payroll, buildings and equipment, and operational costs, but there are also risks.
Traditionally, manufacturing is a core operational function of a pharmaceutical company. When that core function is contracted out, there will be a loss of control of scheduling and of many other details of how a manufacturing campaign occurs. Yet, the sponsoring company remains responsible to the regulatory agencies for the product produced at the CMO. “That was a decision made by the CMO” is never an acceptable answer if there is a question about the quality of a manufactured lot.
Fortunately, there are a vast array of pharmaceutical contract manufacturing organizations. And, for the most part, the expertise that they bring to the table regarding their manufacturing operations more than makes up for any loss of control in most manufacturing projects—particularly when appropriate contracts are in place to protect the sponsor and ensure performance of the CMO.
Criteria to Consider
There is no “best” CMO. Some CMOs are better at a certain clinical phase or at a certain scale. As a project graduates from pre-clinical, to early clinical, late clinical, and commercial, more than one CMO may take a role in API manufacture, drug product manufacture, and labeling and packaging. Some ways of evaluating and ranking possible contract manufacturing organizations include:
Time: How much process optimization does your manufacturing process need before it is ready for a GMP campaign? Do you have release assays, or do they need to be developed? Are there raw materials that will be difficult to source? What do you know about the stability of your active? Once you have talked through the particular challenges of your project, the CMO will be able to give you an estimated timeline.
Cost: The CMO will provide estimated cost in their proposal. In general, you should expect that US/EU CMOs will be 2x to 4x more than CMOs in India and China for early phase manufacture in the range of 10 kg. For Phase 3 and commercial manufacture, other factors should start to weigh more heavily than cost.
Quality: There are 3 formal occasions when your team will be assessing quality at the CMO:
Site Visit Assessment: When your company seriously considers a CMO, a site visit is important. You will be able to assess: staffing levels, staffing quality (if you talk to the personnel on your tour), equipment and facility maintenance, procedures and documentation (if the CMO shares some GMP documents during your visit), and site regulatory and inspection history.
GMP Compliance: Before signing a contract or shortly after, your company’s Quality team will do a compliance audit. This is an opportunity for your team and/or your QP to assess compliance with US and EU GMPs. Areas to focus on include: documentation, materials control, cleaning, maintenance, analytical laboratories, training, and deviation resolution.
Phase 3/Commercial Readiness: In contrast to early phase clinical manufacture, Phase 3 clinical manufacture is predicated on the idea of a pre-approval inspection (PAI) which assesses readiness for commercial manufacturing, conformance to the application, data integrity, and adherence to GMPs. (All the systems need to be in place, even though the PAI won’t occur until after you have made your submission.) In the Integrated Quality Assessment (IQA), FDA will consider: proposed operations, product risk, development and scale risk, previous experience qualifying and maintaining processes, data integrity concerns on applications, and risk of control strategy. So, your Quality team needs to think about how the site will stand up to a PAI even before you begin Phase 3 manufacture.
Project management: To assess the CMOs project management approach, your company needs to think about its own approach to project management. Some companies take the “sit-down restaurant” approach; they order up a manufacturing campaign, and the product is brought to them when it is ready. Other companies take the “burrito line” approach, watching every step closely, suggesting improvements, making requests. Both approaches are valid, but you should match your expectations to the CMOs systems and approach, and it may be that some CMOs aren’t a good match for your company.
Team and Experience: Meet the personnel that will be assigned to your project (technical lead, analysts, project manager) and the site management (site head, head of manufacturing, head of quality, head of analytics). Your company is making an important hiring decision, so consider it carefully. Understand how available these personnel will be to your company, their experience level and motivation level.
Services: Does the site provide all the services you require (e.g., development, manufacturing, materials management, QC, QA, regulatory, stability). For example, does the CMO do a lot of process optimization, or does it typically receive processes that are mostly ready for GMP manufacturing, and how does that level of service match with your project’s needs?
Protection of IP: What are the CMOs policies and practices to ensure the protection of your company’s trade secrets?
Building the Relationship
A good relationship between your company and its key vendors is built in stages. These include:
Request for Proposal: A good request for proposal provides all the relevant details regarding your manufacturing process, scale, clinical or market demand, product specifications, and timing. It should be formatted to allow the CMO’s proposal writers to find the information they need easily. Think carefully about what the CMO really needs to know to write a good proposal. For instance, some CMOs ask for batch records if you have them, but that is really too much information. BRs from previous manufacturing runs should be provided during technical transfer.
Contract: Some CMOs operate based on the proposal as a contract. Consider the language of the proposal and whether you feel it has all the protections you need. You may need to amend. You will likely follow up with a Quality agreement and, for later stage projects, a supply agreement.
Transfer: This is the point that you provide all the technical information the CMO will need to run your process and your assays. Ideally, you have technical reports that summarize and trend the data from your work so far. Executed batch records from previous runs can be helpful, also. In response, the CMO produces either clearly written master batch records (MBRs) or MBRs combined with a written process description.
Manufacturing Campaign: How the manufacturing campaign is managed varies from hands-on (with extensive use of person in the plant) to hands-off (“Let me know when the batch is ready for shipment.”) Manufacturing campaigns will be the subject of a future PharmaTopo post.
Maintaining the Relationship
Your CMO has a lot of information that can help your project succeed: trends and problems that you may not be aware of in your manufacturing process, future scheduling of the CMOs manufacturing suites, problems obtaining raw materials, etc. You will want to ensure whatever approach that you take (hands-on or hands-off) that you have a clear idea about all this information that may affect your company. Arrange appropriate meetings in preparation for manufacturing campaigns, during the campaign, and afterwards to ensure good communication. Also, meet periodically with the business development team—since they are in tune with the manufacturing schedule—which is important as you consider future campaigns.
Many CMOs contribute almost unseen value to a project. It’s important to notice when that occurs. Here’s a story from a manufacturing campaign at a large Chinese CMO near Shanghai. Our process produced API for our lead drug candidate, and there was one step that we understood less well than we should have. The CMO’s technical lead came to us saying that this step should be run in a certain way. Our CMC team said, “No.”—we know how this step should be run. The CMO’s technical lead went back to data from previous process runs and used data mining to show that there was an effect that we needed to consider, or the batch could fail. The key point is that many personnel at many CMOs would have given up after they got a no, but this technical lead was so invested in our project, she was willing to go above and beyond to ensure our success. When you find CMOs like that, ones that provides extra unseen value, you will want to bring back repeat business to them.
[1] www.cphi.com
Disclaimer: This post is reprinted from PharmaTopoTM. PharmaTopoTM provides commentary on topics related to drugs. The content on this website does not constitute technical, medical, legal, or financial advice. Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.
