Source: Singota Solutions
By William Powers, Singota Solutions
Meeting drug development timelines — in particular, filling the first Phase 1 batch for an injectable’s clinical trial – is critical. Producing that initial batch requires the CDMO to gather information from a pharmaceutical client about its drug substance, drug product, and analytical methods. If the information is unknown, incomplete, inaccurate, or not available in time to support CDMO project timelines, manufacturing will be delayed.
Accordingly, the strength of the technical package an organization submits to its development and/or manufacturing partner — its accuracy, robustness, and completeness — is a significant factor in meeting a fill project timeline. Companies may approach CDMO partners with different levels of understanding regarding what should be included in the technical package. Individuals negotiating the project timeline may not be familiar enough with key technical drivers in the project or the breadth and depth of a required analytical method, for example.
Then, when the project kickoff meeting assembles the supporting teams from both sides, bringing an array of technical capabilities to the table, seemingly minute details can surface that lead to dozens of questions or concerns. In short, before project onset, CDMOs don’t always have enough information or the appropriate experts present to catch these details. In some cases, the client needs to improve its sourcing of that info; in others, the CDMO must be clear in articulating the information it needs.
How Problems Arise
First-time development projects are among the most susceptible to these issues. Smaller or emerging organizations may be less prepared due to smaller staffs and fewer resources, while larger companies have the benefit of more SMEs and more available resources. The heavy lifting of early drug development work is increasingly handled by small companies, which lack the benefit of a huge stable of scientists, have stakeholders to appease, and — almost always — work under the cloud of an ambitious timeline. This can lead to a technical package that is not as complete and accurate as both partners would prefer.
No particular shortcomings stand out from the rest, as different organizations arrive at the Phase 1 batch via different pathways. A small drug developer may have been working with an academic lab to develop their product and methods, and believes it understands its molecule well, but transfer to a full GMP lab subjects the project to stricter practices (e.g., day-of-use check, calibration, etc.).
Suddenly, the data provided by the client does not match what is occurring as the CDMO attempts to replicate the client’s efforts, and questions arise because producing a few milliliters of a compound is vastly different from producing a liter. A detailed conversation at the project’s outset between the scientists who completed formulation work and the CDMO avoids many such issues, or at least prepares both parties for problems that may be anticipated.
Common Hurdles and Red Flags
Issues exposed during fill/finish typically are related to three areas: analytical test methods, formulation, and drug substance. The following are just a fraction of the questions relevant to a technical package as a client and CDMO begin their collaboration:
- Analytical Test Methods
- Are they well documented?
- Have they been performed more than once?
- Was the lab that performed the method development experienced and cGMP compliant?
- Were the instruments used properly maintained and calibrated?
- Are there differences between the API lot used for method development and the lot the CDMO will transfer in and use?
Analytical methods must be meticulously recorded, with sample preparation being a principal concern. Does the sample need to be diluted or maintained at a certain temperature? Some drug substances must be prepared and analyzed quickly using (for example) high-performance liquid chromatography (HPLC), or their properties may change. Or perhaps lab work was performed using a different brand of HPLC instrumentation than will be used on the production floor? Test instruments are extremely sensitive and complex, so if anything is amiss, the testing will not produce the same results. The point is, every detail is subject to change.
- Have there been solubility issues?
- Were all process elements recorded (e.g., the client may have heated the compound to 40°C for formulation and that element was not noted).
- How big is the jump in volume from lab bench quantity to the proposed batch size for the fill?
- Are there now prescribed excipients that were not tested on the lab bench with the client?
- Is the order of addition spelled out?
Scale-up and the robustness of documentation addressing formulation usually are interrelated issues. If questions like those above remain unanswered, the CDMO may need to perform additional bench testing to further characterize the material. For example, the client may state it only has mixed its compound in small amounts but experienced no issues. However, literature relevant to the materials indicates the excipients used sometimes do not work well together. The substance may not dissolve as intended. Thus, transparency early and often is key.
- Drug Substance
- Do one or both partners have previous knowledge about and/or experience with the material?
- Have potential degradation factors been identified (e.g., time out of refrigeration, hydrogen peroxide sensitivity, changes over time in viscosity and flow characteristics)?
Ultimately, any of these issues can significantly impact production timelines. The two parties must meet and figure out the problem: Did the CDMO lack information, did it err in formulating the drug substance, or is the test method flawed? Hours turn into days turn into weeks.
Utilizing an engineering batch is a smart way to identify processing problems in advance of the GMP fill, but it adds time to the project timeline, which can be a stumbling block for some development projects. An important trade-off must be evaluated by the client: a little more time added to the schedule versus a potential significant timeline delay if a problem is identified during the GMP fill.
Where Does the Time Go?
Even in the event everything goes flawlessly — analytical methods and formulation notes are thorough; drug substance is well-understood — final manufacture (formulation and aseptic fill) is among the last gating items before clinical trials. And companies usually cannot avoid clinical trial scheduling deadlines without great expense. For this reason, it is paramount to engage a CDMO partner as early as possible, vetting that partner for its agility to manage an unforgiving timeline.
Hopefully, some “slack” time was built into the project but, more often than not, that is not the case. Frequent, regular, transparent, and clear communication between the client and the CDMO may cause both to recognize the potential for a delay in the fill target date.
Sometimes a CDMO can apply extra resources or overcome a slip in schedule. Or, for example, another company may ask the CDMO to be squeezed in for a fill. Perhaps they are a previous client and the CDMO already has a process in place and the necessary materials available. The CDMO can fill the vacated slot and serve both clients optimally. While this is an ideal situation and such accommodations are the exception rather than the rule, prospective developers will want to know if a CDMO has such capability.
Injectable development projects demand accurate, timely, and complete technical information about a drug substance and its associated test methods to be shared with the CDMO to achieve desired timelines/fill date. The keys to successful aseptic fill/finish partnerships in service of those timelines mirror those of most industry partnerships: engage early and communicate clearly.
Toward this end, small or first-time drug developers are smart to retain an experienced CMC consultant (in-house or an outside expert) skilled in navigating the steps of injectable fill/finish development projects. To learn more, visit us at singota.com and follow us on LinkedIn.
About the Author
Mr. Powers is currently a Senior Management Consultant for Singota Solutions, having directed the company’s business development group in the past. He has been active in new product development over the years not only in pharmaceuticals, but in the electronics and renewable energy fields, as well.