In 2020, the FDA approved 53 novel therapies – the second highest number in 20 years.1 Key to this achievement was a focus on reaching clinical end points as well as compliance with good and high-quality manufacturing practice. Well-orchestrated cGMP manufacturing can help avoid manufacturing issues primarily in the clinical phases as well as in discussing potential projects with partners or key stakeholders.
The key to successful development and guiding a drug to the approval stage is early planning. Making the right decisions early will also provide a competitive advantage. A checklist for the different phases and actions that need to be taken is also effective in helping avoid unnecessary costs and delay, streamlining the entire process, and enabling product quality, compliance with budgets and schedules and later success on the market.
Preliminary planning must be realistic
Developing and preparing a drug for approval is complex, requiring cooperation among many different organizations, companies and individuals. A realistic timeline that takes into consideration all critical points of the process is essential. Begin with a consultation with your clinical research organization (CRO) to check that all relevant milestone dates are viable.
Knowing the unique active pharmaceutical ingredient (API) properties is important when discussing the project with your partner responsible for performing the clinical studies and manufacturing. This includes knowing the processes involved, especially any special ones involved such as suspension filling. Being able to manufacture enough of the API for a timely and effective trial run is crucial.
Manufacturing knowledge is also important. A manufacturing partner needs to handle an active substance safely and use the existing infrastructure for proper containment. Know how the API and excipients will react in a cGMP clinical manufacturing setting as well as the ability to provide cGMP grade material with auditable certificates of quality is essential. So too is understanding local regulations which demands the need for accurate documentation if there is a desire to manufacture in another country.
Contact regulatory authorities early to inform and receive advice for submittal about the molecule, dosage form and packaging being submitted. The complexity of the manufacturing process needs to be considered in early planning stages. Determine whether it is more efficient to outsource manufacturing to a contract development and manufacturing organization (CDMO) that can handle a complex process and guide it to successful completion.
A broader view of primary packaging: API and materials
Primary packaging is essential in preparing a drug for market supply. An audit of your partner is important in ascertaining all components and excipients are cGMP quality and can be sourced in time. This is also true for the API.
Packaging can be two forms: standard or non-standard. With non-standard packaging the quantity and quality of source material is even more urgent. Consult a device developer to help determine whether an injection system is adapted to a specific drug. With standard packaging, you need to think ahead. Vials, for example, come in different sizes. Thus, be certain that the vial will fit the manufacturer’s filling lines.
Consider a primary packaging plan for later-stage injection device design, e.g. a prefilled syringe. Important benefits of such planning include shorter time to market, reduced API loss and increased attractiveness for patients leading to a competitive advantage. Are there specific indication or patient needs that will need to be met. Pediatric use cases or specific indications may require stability studies in 0.5ml syringes or silicon free polymer packaging materials. Will it be difficult to source these components on time?
There are also economic reasons for considering syringes. A parallel development strategy in a syringe can increase value when licensing, especially if the necessary studies, tech runs, and validation and registration batches have been done.
Finally, one point that is often overlooked is API sourcing. Determine in advance whether your API will need to be imported or exported for manufacturing and trials. If you need to import your drug substance and export the filled drug product, certain countries may require specific information or documentation to allow your API or clinical batch to pass through customs. Make sure you identify any special country-level regulations to ensure your drug substance and filled clinical supply arrive where they’re needed, when they’re needed.
Good contracts make for good partners
Before starting clinical manufacturing, legal quality and supply agreements with multiple partners need to be verified and signed. Legal standards cover a wide range of topics. Intellectual property rights are also critical. To meet cGMP quality requirements you have to understand what is required when the process moves from the lab to clinical cGMP manufacture. A formal audit of the company’s quality standards is necessary, which can mean extra time, so plan accordingly.
The right development practice and analytics
Regulatory authorities have established stringent standards for risk management based on ISO standards, including cGMP. Companies need to flag Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) so that the CDMO is aware of them.
It is also important to think about scaling-up for later trial stages and market launch. An effective manufacturing partner will root out any issues during that process and offer concrete approaches, especially if a company has been using external lab services for tests or components. The company itself must determine how data is shared and have robust standard operating procedures for the transfer of analytical methods.
Starting cGMP clinical manufacturing
Once the clinical manufacturing process begins, any interruption can become extremely costly. Technical runs with placebos should be made to determine fill volume specification and to see if there are any problems.
The time needed for visual inspection and labeling should also be measured prior to starting. A sponsor should request from a manufacturing partner the time required to complete release testing to determine how long it will take to get a formal batch release. What storage requirements are you going to need after filling or between steps? Will enough -20 to -80 chest freezer capacity be available on-site for your project?
If lyophilization is being considered, start primary freeze-dried stability studies early. Frozen formulations are often used to extend the time of unstable biologics such as large proteins.
Another aspect to consider is automation, with some exceptions. For example, early phase toxicity studies or filling small batches can be done by hand. For larger volumes, however, automation offers many advantages, notably speed and safety. When using filling machines, it is important to know what systems are in place including capacity in terms of speed and formats.
Choosing the right partner
Because manufacturing a drug and submitting it for approval is complex and expensive, many companies choose to outsource the process. Be realistic in your timeline. Ensure that the candidate partner can do the work within the schedule and budgetary limits and handle the compound safely.
Quality assurance is a key criterion. The quality audit system needs to match the contracting company’s quality assurance expectations such as the ability to perform the necessary analytical tests. Your partner should also have the drug sponsor’s packaging configuration and be able to source it in time. As you can see, there are many intangible aspects to make for a successful project, and that is why the use of the checklist is so important.
1 Nature. 2020 FDA Drug Approvals. 5 January 2021. Accessed 22 June 2021. Available at: https://www.nature.com/articles/d41573-021-00002-0
Download our eBook for a strategic 6-step checklist that will help your team:
- Rapidly and efficiently scale production of your API
- Proactively address potential logistic, technical, and regulatory hurdles
- Identify the right CDMO partner to help you get your product to the clinic