For pharmaceutical companies both large and small, the challenges involved in developing new drugs are growing steadily. Regulatory requirements are becoming more complex, and the processes involved have followed suit. Even more innovative manufacturers have to struggle to find a straight path through the many issues involved. Indeed, they often have to deflect their attention from their drug candidates in order to deal with a wide range of issues such as financing and regulatory approval, rather than focus on their drug candidates.

In the process, formal GMP requirements for sterile manufacturing are often underestimated or overlooked entirely, causing delays in starting trials or forcing companies to return to investors for still more funds to meet an unexpected problem. Given the proper tools and support, many of these challenges could be avoided altogether, freeing up drug makers to concentrate their efforts on the development of their products. This is particularly true for both small and medium-sized biotech companies, which often lack the resources to begin clinical manufacturing with little risk. One solution is partnering with a Contract Development and Manufacturing Organization (CDMO) with the experience and capacity to shoulder the many different tasks involved in clinical manufacturing.

Reality is never as straight forward as its model. Pharmaceutical companies have to engage in a very wide range of processes in order to meet the challenges facing the industry. Some processes are straightforward and simple, while others are highly complex and circuitous. Thus, when seeking partnerships with a CDMO it is important to select one that has as significant experience with these processes. The goal is for the pharmaceutical company to be able to focus its resources on essential tasks. This is the best way to achieve a successful outcome. The profile of any candidate CDMO will be a function of what the requirements of the contracting company are. The following checklist will offer insight into the drug development process, and can act as a roadmap to success in finding a suitable partner when envisaging the clinical manufacturing of a new product.

The foundation: a realistic timeline
Early planning is the key. Before beginning the actual manufacturing process, there are already a range of measures that can be implemented during the clinical testing phase. First and foremost is the need to draw up a realistic timeline to help support a smooth procedure for all future processes. This needs to be done in advance of a formal submission of an investigational new drug file (IND), or an investigational medicinal product dossier (IMPD) to an authority. It also comes before setting the agenda with a Contract Research Organization (CRO) or a clinical trial site. This first step demands experience since the creation of a realistic timeline requires extensive understanding of the product. What does this mean in real terms? The first step is making sure that all the parameters required by regulatory authorities are determined. These include class of compound, formulation and presentation. The requirements regarding sterile filling, stability, bioavailability and patient safety are also clarified. This information is readily provided by the regulatory authorities, along with explanatory guidelines and a support service.

Establishing GMP production also demands in-depth manufacturing knowledge of the active substance and the ultimate product. Certain quality requirements must be established from the start as well. For example, not all substances are safe to handle. Therefore, what will the level of containment have to be? Do you need safeguards in place for material preparation? What local site registration documentation is needed? How has the API been solubilized? Are there unique properties or process requirements such as the addition of organic solvents, nitrogen overlay, or suspension filling? Indeed, the more complex the substance, the more complicated the filling process. Therefore, the profile of the CDMO will have to include quite a few specific factors, notably physical capacity and expertise. It is important that this be considered within the schedule to avoid delays in the launch phase.  

Primary packaging: making the right choices can reduce risk and cost 
When seeking primary packaging, one has to balance economic factors with effectiveness. The first question that needs to be addressed is whether the drug should be filled in a standard package or a customized one. It is important to think long-term at this point. Working with a state-of-the-art cartridge or a company that has an innovative novel injection device may be very tempting at first glance, but when it comes to clinical filling, looking for a firm within the industry that has properly automated lines that can fill that format efficiently would be helpful. Looking ahead, the question “can primary packaging be used for Phase II and Phase III?” is important to consider. That is why choosing a newly designed form of delivery always comes with some level of risk that will be necessary to take into account early on in the process. Even if you do find a partner for the filling, you may need a unique media fill to qualify the filling line. This can generate additional costs and delay your manufacturing. An experienced partner will know this and can offer some valuable recommendations, for example, the choice of a certain type of stopper that produces significantly less particles with your particular process.
Another factor is the sourcing of components and excipients. Experienced partners will have established suppliers for common excipients, which may differ from the ones used in the laboratory setting. Large-scale GMP procedures require formal proof of quality manufacture with documented and certified specification limits. This is done using formal audits, which will have to be performed in order to establish that the clinical manufacturing project is in being handled correctly. The other option is to cooperate with the CDMO’s existing sources.

In addition to the potential pitfalls with packaging and excipients, one should look carefully at the actual location of the filling. Before starting the project it is important to ask how best to import and export your API and various components to the country where the manufacturing will take place. Usually, manufacturing in the same country where the trial is to take place is the simplest solution. If this is not possible, you have to investigate how to get regulatory approval in your trial country, and extensive international customs documentation will be needed for shipping. Do not overlook the fact that after compounding and filling, the value of the product will have changed. Experience shows that valuable days or weeks can be lost due to missing documentation for in-transit clinical trial material.

Legal and quality issues
When outsourcing clinical manufacturing, the contract between the two partners should be ‘airtight’ from a legal standpoint. A number of areas that are covered by the agreement include being aware of, and understanding, all of the manufacturer’s quality requirements for GMP filling. Ideally, an agreement by the partner to commit resources and set a date for a formal audit by an external CDMO is preferable. Confidentiality and development service agreements also have special requirements. Risk management, liability, and IP ownership are all issues that need to be explored and analyzed prior to starting any work so that both parties have a common understanding of how they will be anticipated and properly addressed.

Most biotech companies are understandably cautious when entrusting their valuable, and often rare API, as well as their critical timelines to a CDMO. This is why any agreement is considered legally binding. A CDMO can act as a reliable partner to a drug company as long as it does so within the parameters of its capabilities. Thus, the interests of each party to the contract are considered and written into the clauses. Contracts are an overriding business requirement and should not be underestimated.
Failure to take details into account can result in bottlenecks later on, therefore, negotiating these agreements should be given sufficient time. This process can become even more complicated if more parties are involved in the negotiations including consultancy firms or third-party device companies contracted for a project. Each will have to be included in the contract, resulting in a serious time delay in reaching an agreement.

Successful launch of the clinical manufacturing project
Until now we have looked only at issues that deal with pre-manufacturing.  Let us now turn to the GMP clinical manufacturing project. Even if everything seems ready to go, it is important to remember the old saying: “Haste makes waste.” There are a number of preparatory measures that can be implemented to support speedy and streamlined processes.

As in all good science, measuring the quality of the process will be a key to final success. The FDA has issued a set of guidelines and recommendations for good development practice (ICH Q8/Q9/Q10), that provide many answers to questions a company might have at this stage. A useful concept that is frequently used in modern companies is ‘Quality by Design’. This holistic, science-based approach integrates set quality goals, risk and other criteria into the very design of the product. With Quality by Design, Critical Quality Attributes (CQAs), and Critical Process Parameters (CPP) of an API are identified. Determining these values mean being able to control variability within a repeatable range of specifications. Therefore, manufacturing can be done within the required quality parameters. Some CQAs, however, may only become present during the scaling-up phase. For example, when mixing and compounding in the lab, proteins can become denatured; though this is rarely seen at the lab scale. Scaling up the process requires different pumping procedures, which can produce sheer forces that may become a serious problem. Other problems can arise when an API comes in contact with different materials like stainless steel or single use polymer syringes. Nevertheless, many tests need to be done, including standard IPC chemical analytics, customer specific testing and bioburden and endotoxin testing.

Quantity is money
A favorable agreement with a CDMO would include key performance indicators (KPI). Fundamental indicators are loss of and variation in API filling volume. This seemingly obvious issue can generate long negotiations. Here is what you should know: Scaling up clinical batch size results in significant losses in API due to dead space in longer tubing and connectors, in-line filtrations and destructive sampling. Companies tend to focus on the in-process losses, but then are surprised to learn that losses due to their sampling requirements are much greater. Creating an agreement on acceptable levels is often an eye-opener for many less experienced firms that might not have realized just how much API is needed for GMP production. It is yet another reason to look for a CDMO with dedicated lines designed for clinical manufacturing where the goal of API loss minimization has been integrated into the design of the filling line and cleanroom, both due to the process and the necessary sampling. Having a placebo formulation without active drug is a good idea since many technical tests can be run without using, and thus losing, API. After performing a technical run, many pieces fall into place and reasonable assessments can now be made, such as volume specifications and the percentage of units passed after visual inspection. Downstream topics need to be addressed from the start and include: How long do the samples stay for visual inspection and are there special secondary packaging needs? Is there enough data to support these processing and holding times? A related issue is collecting data to qualify holding times for active drug substance.

One more point related to API needs to be covered. Complete testing and documentation for a formal quality batch release by the CDMO can take several weeks depending upon the methods used. The testing of the parameters generates data that is crucial for the filling process, but it will also mean producing significantly more API than first planned. This, in turn, can put pressure on the timetable and the budget.

Lastly, certain decisions made by development firms can speed up early phase development only to cause later delays. One such issue is formulation. Going into Phase I and II with frozen liquid can help prevent stability issues arising during development and early clinical filling. However, the team has no chance to gather data on final presentation state for later phases. Starting the work in parallel on a re-formulation or lyophilization cycle development may mean costs earlier on, but help avoid them at a later phase.

Time and resource management
As we have seen, elaborating a detailed checklist is an important key to successful GMP clinical manufacturing. One should never underestimate the time and resources needed for efficient processes. One solution might be a checklist on hand that will support your long-term planning. Smooth execution of your clinical manufacturing project relies on several important pillars. The first is a realistic schedule that avoids the need for rushing. Second, you will need to be well versed in all the regulatory provisions.

Finally, be aware of any risks involved, e.g., non-standard packaging solutions or loss of API. All companies developing drugs, from the small biotech to the major pharma company, can benefit from partnering with a CDMO with experience in handling these peripheral, yet crucial aspects of clinical manufacturing. A CDMO has the expertise and know-how in providing long-term and detailed planning, meeting high quality standards, implementing regulatory guidelines, and the human and physical infrastructure to meet all the challenges of highly complex processes. 

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Dr. David Brett joined Vetter in 2010 as product and service manager with a focus on innovation in injectable drug-delivery systems, clinical development and commercial manufacturing. He became team leader of product and service management in 2015, and is responsible for the development of Vetter’s service offering to fit customer requirements.