In 2017, a record 46 submitted drugs received approval from the American regulatory agency FDA. One of the reasons for this success is the reciprocal commitment between the sponsor and regulatory bodies to maintain a high quality of applications. Both entities focus on reaching clinical end points as well as compliance with good and high-quality manufacturing practice. One way to help your company engage in good cGMP manufacturing and avoid common manufacturing issues is through the use of a thorough checklist for the clinical phases. This list can be used when discussing potential projects with partners or key stakeholders.
The key to successfully developing and shepherding a drug to the approval stage and beyond lies in careful planning right from the start of development. Any and all issues that may arise during the process should be considered during this planning phase. For gaining competitive advantages, it is crucial to make the right decisions early. In this regard, ideally a company will have a checklist to keep track of the different phases and actions that need to be taken. The effort put into this planning leads to the avoidance of costs and delays during the whole process. As we will learn, it is a way to streamline the entire process and enable product quality, compliance with budgets and schedules, and even its later success on the market. Here is a helpful checklist when developing a drug product and designing a manufacturing strategy.
Developing a drug and preparing it for approval is a complex process requiring the cooperation of many different organisations, companies and individuals. This means first and foremost, setting a realistic timeline that seriously takes all critical points of the process into consideration. Thus, an important first step then is to consult with your CRO (Clinical Research Organisation) to check that all relevant milestone dates are viable.
When discussing the project with the partner responsible for performing the clinical studies and manufacturing, knowing the unique API properties in depth is important. This includes ingredients used to manufacture the product such as organic solvents or nitrogen overlays, and, of course, the processes involved, particularly if there are any special ones involved such as suspension filling. A partner must also be able to manufacture enough of the API for an effective trial run that is on time.
Looking ahead, a biopharmaceutical company must have deep manufacturing knowledge as well. The company or the Contract Development and Manufacturing Organisation (CDMO) contracted to do the work must be able to handle an active substance safely and have the infrastructure for proper containment. It must also know how the API and excipients will react in a cGMP clinical manufacturing setting. Such chemicals will have to be sourced in increasing larger quantities depending on the phase of the study. The supplier also needs to provide GMP grade material with auditable certificates of quality. It is not uncommon to encounter issues when trying to find a supplier that produces beyond lab grade. Some companies would like to manufacture in another country which entails understanding of local regulations and, most certainly, generates accurate documentation.
Besides the partners and suppliers, the company planning a submission for first-in-human studies should contact regulatory authorities as soon as possible to inform them about the molecule, its dosage form and the packaging being submitted. In return, they should receive advice for submittal.
Another aspect that must be included in early planning stages is the actual complexity of the manufacturing process. A question to challenge the organisation with is‘ whether it is more efficient to outsource manufacturing to a CDMO that can handle a complex process and guide it to the end?’
Primary packaging, while having impact on a later stage of manufacturing, is one of the leading issues in preparing a drug for market supply. Thus, it needs to be addressed thoroughly and with care. There are two aspects that need attention. First is the manufacturing itself. The biopharmaceutical sponsor will have to audit the partner or CDMO to be certain that all components and excipients are cGMP-quality and can be sourced in time. This is also the case for the API.
The second is that the packaging can be divided into two chapters: in standard and nonstandard packaging issues. With nonstandard packaging the quantity and quality of sourceable materials becomes even more urgent. A drug might require a cartridge for self-administration, or even a syringe with a dual chamber system for freeze dried API’s. In such cases, only handfilling may be possible. Consulting a device developer at this stage can help determine whether an injection system is adapted to a specific drug.
Note: Even with standard packaging, companies must think ahead given vials, for example, come in different sizes throughout the world and with different neck sizes. Therefore, if a company is planning to scale up its product, it must be certain that the vial will fit the manufacturer's filling lines.
While considering primary packaging, it is also important to plan for laterstage injection device design. Typically, in early clinical phases, a drug is released in a vial which provides more flexibility for experimentation with dosing regimens. Considering early syringe clinical development, however, has several important benefits such as shorter time to market, reduced API loss and increased attractiveness for patients. Competitors may have already marketed a similar product in syringe form and keeping abreast of the market is, therefore, crucial. The use of a platform approach to development could gain an average of 18-month head start.
There are also concrete economic reasons for envisaging syringes as a packaging. Vial losses of API through manual overfill can accumulate to considerable sums. In one case, a yield increase of 2 per cent per batch of a protein worth €0.89 per gram resulted in savings of €650,000 per year when the drug was manufactured in a pre-filled syringe as compared to a vial.1 Additionally, a parallel development strategy in a syringe can increase the value of a license to another partner. This is especially true if the packaging selection, feasibility studies, lab studies, tech runs, stability and clinical batches, followed by validation and registration batches have all been done.
A final point to consider is whether the API will be imported or exported for manufacturing and trials. The target country may have special regulations and the API will have to pass through customs smoothly. A good idea is to discuss the matter with a consultant or a CDMO.
Before the clinical manufacturing can start, companies must discuss, verify, and sign legal quality and supply agreements with partners. Because this can involve multiple partners, it is worth encumbering extra time to make sure everything can be fully settled. Legal standards cover a wide range of topics such as jurisdiction in case of a court case. One must remember that manufacturing a drug also involves "soft" topics like intellectual property rights which can have important repercussions.
In order to meet cGMP quality requirements, a company must understand what is required when the process moves from the lab to the clinical cGMP manufacture. Time and resources have to be invested into a formal audit of the company's quality standards which can cost a little extra time if the manufacturing is entrusted to a manufacturing partner. Finding and agreeing on an efficient path forward is not always a simple matter.
Regulatory authorities have established stringent standards for risk management based on ISO standards, including cGMP. They are numbered ICH Q8/Q9/Q10 and cover Pharmaceutical Development, Risk Management and Pharmaceutical Quality System. Essentially, they include the overall manufacturing space and look at critical aspects of the entire supply chain and process parameters.
The authorities generally demand that Quality by Design methodology be applied to define and measure those aspects and parameters and deliver effective risk assessment. A manufacturing partner must be able to provide those figures. Even with standard operating procedures, certain parameters such as concentrations of one substance can change. Companies need to flag Critical Quality Attributes (CQA) and Critical Process Parameters (CPP)so that the CDMO is aware of them. This not only generates product quality, but also avoids time-costly events later on in the process implementation.
In the early stages, formulation and stability trials are done at lab scale. However, it is a good time to think about scaling-up for later trial stages and market launch. This may not require greater amounts of data. The job of an effective manufacturing partner is to root out any issues that might crop up during that process and offer concrete approaches. This is particularly important if a company has been using external lab services for tests or components which is done quite frequently. The company itself must determine how data is shared. It must also have robust standard operating procedures for the transfer of analytical methods.
Once the clinical manufacturing process begins, interruptions for overlooked details can become extremely costly. The pharmaceutical sponsor needs to ensure that the API amount is sufficient to cover all process steps in the scale-up. For example, the cGMP scaleup process may cause some API line losses from longer tubing and in-line filters. Destructive sampling and the additional API that may be needed for further stability or holding time testing should also be considered. Catching any issues at this stage can save a great deal of time and expense later on.
Technical runs with placebos should be made to determine fill volume specification and to see if there are any problems, e.g., filter clearance, air bubbles, or standing times that need resolving. While highly recommended, some companies might choose to avoid this step.
The time used for visual inspections and labelling should also be measured prior to starting, particularly if the product requires special labelling. The length of time a product stands between process steps could require more stability testing or refreezing. A pharma sponsor company should request from a manufacturing partner the time required to complete release testing to determine the time it will take to get a formal batch release.
Finally, if a company is considering a later lyophilisation of the product, the time to start some primary freezedried stability studies is now. Frozen formulations are often used to extend the time of unstable biologics such as large proteins. However, freeze thawing may not be practicable in commercial settings and, thus, the need for freeze drying. If a company is considering this approach, then planning at an early stage is important, especially when it comes to the choice of a manufacturing partner.
Another aspect to consider is automation: The global drive towards greater automation includes the pharmaceutical industry. However, there are some exceptions that need to be taken into account. For example, early phase toxicity studies or filling small batches i.e. under five-hundred units– can be done by hand. For larger volumes, however, automation does offer many advantages, notably speed and safety since automated lines tend to reduce human error. Of course, filling machines are different. It is always important to know what systems a manufacturing partner has in place and what their capacity is in terms of speed and formats. By factoring in the size of vials or lyophilisation where appropriate, a company can get an accurate estimate of how much time will be required to get all the batches manufactured and ready for submission.
Manufacturing a drug and submitting it for approval is a complex and expensive process. That is why many companies choose to outsource to a partner that can take charge of a number of stages in the process. The over arching question that needs to be answered before any signing of agreements is whether the candidate partner actually has an available filling slot for the drug and can do the work within the schedule and budgetary limits? Here again, being realistic about timeline estimates is of utmost importance.
The chosen manufacturing partner must be able to handle the compound safely. At best, they will have had experience with a similar API. Quality assurance is another key criterion. The quality audit system should match the contracting company's quality assurance expectations. One aspect of this is the ability to perform the necessary analytical tests. Further a CDMO needs to have the drug sponsor's packaging configuration or be able to source it in time. Finally, there are more intangible aspects to make for a successful project. Many of them include project management,customer service, and response time to communication.