By Louis Garguilo, Chief Editor, Outsourced Pharma
Ours is a responsive Editorial Advisory Board, but no question posed to them elicited the range and rate of response as this one:
“What are the biggest challenges you face with outsourcing fill finish services – what keeps you up at night?”
Chances are, many Outsourced Pharma readers are also experiencing the same challenges board members told us about, and I’ve listed below for you.
Some Defining To Do
Let’s begin, though, with some defining. For the most part, the biopharma industry uses sterile and aseptic fill finish interchangeably, but note this paragraph from Difference.Guru:
“So what is the difference between aseptic and sterile techniques? Aseptic techniques are used to promote asepsis, a condition that is clear from harmful pathogens, viruses, parasites, fungi, and harmful spores. Sterilization is the process of eliminating living microorganisms of all shapes and forms.”
Of course, different molecules and programs – and there are more variations today than ever before – call for different requirements. Here are two additional definitions, these this time from industry sources (click on titles for more detail):
Aseptic Fill & Finish: “Aseptic filling is an aseptic process that requires the close coordination and complex interaction between personnel, sterilized product, the manual fill/finish equipment system, cleanroom and support facilities (Class 10,000/Class 100), and sterilized filling components.”
Fill Finish Processing: “After upstream bioprocessing, [the] formation of the active agent by cell culture or fermentation, and downstream purification; this is when the final product has the greatest value, and, thus, the most to lose to a product failure … and any mistakes at this point can potentially lead to product misformulation, contamination or improper packaging.”
The Board Responds
I’ve done minimal editing to these selected responses from board members regarding the current challenges they are facing in outsourcing fill finish services, and working effectively with their external partners.
(1) The First five (Vimal Gandhi, AstraZeneca )
- Matching production volume needs in clinical/ development phase with commercial phase. Early on, one needs small volume but flexible schedule. And then for Commercial one needs the CMO to adhere stringently to forecast but have accept some upside if needed.
- Providers don’t have the full range of analytical-testing capabilities they say they do, and therefore cannot release product. Having capability to do 90% of tests is great, but it forces one to have to qualify an alternate site to perform the remaining few tests.
- CMO’s continue to overpromise and under deliver in terms of product tech transfer, and completion of PPQ [process, performance, qualification] runs. The ability to balance timing and available capacity with project management resources continues to be an obstacle contributing to the challenge of meeting timelines.
- We should replace manual visual inspection of prefilled devices with automated processes, so that we remove the manual process and reduce time and opportunity for error.
- There is currently a lack of long-term storage space for unlabeled vials at CMO facilities.
(2) Specific Challenges: Cell Therapy Field (Bernie Huyghe, Allogene Therapeutics)
- DP [drug product] fill has to take place at the same facility as DS [drug substance] production, and therefore all operators at the CDMO must be specially trained for both.
- Cells are formulated in cryo-preservation, which limits fill time before cells lose viability if yield is high enough; division into sub-lots is needed.
- Labeling has to occur prior to cryo-preservation, making visual inspection difficult, especially when trying to comply with Annex 1.
(3) Specific Challenges: Antibody Drug Conjugates (Michael Mulkerrin, ADC Therapeutics)
- Finding a CMO with the capability to fill an ADC in the first place is still difficult. Very few providers have the capability, and then;
- There is limited capacity at the providers with the capability.
- Assay transfer is typically the next level issue. The coordination between analytical and manufacturing is typically less than optimal. While we press for manufacturing as quickly as possible, the analytical services cannot execute the transfer in time to meet the manufacturing timeline.
(4) And About That Data (Anand Ekambaram, Merck)
- Annex 1 challenges; and
- Finding the right capacity for our projects; and especially:
- The need for more and coordinated data sharing and analytics. At present, most of our data exchange – specifically production data – still happen manually. How can we integrate our IT systems so that we are able to obtain the same kind of real-time process monitoring and analytics at our providers, as we are for our internal sites?
(5) From The Consultants (Bikash Chatterjee, Pharmatech Associates; Peter Bigelow, xCell Strategic Consulting))
These challenges consistently creep up with fill-finish operations:
- Analytical method tech transfer and execution – the ability to handle Laboratory Investigation Reports (LIR) in a timely manner to minimize product- and business-risk exposure.
- Deviation and CAPA systems - Root Cause Analysis (RCA) is constantly poor in most CDMOs I run into universally.
- Visual inspection remains an issue; we should be moving to more automated processes.
- Hiring, training and motivating excellent operations personnel at CDMOs is important, particularly because the variety and number of projects outsourced by biopharma continue to increase.
- Making facility improvements and technological advances, without having extended shutdowns, is important.
- The industry as a whole needs to better ensure we have improved and consistent quality of supplied materials, including raw materials, glass, etc.
(6) More From Big Pharma (Todd Mabe, Merck)
- Annex 1 changes need to be studied and addressed, and the impact to the internal and external network need to be assessed.
- There is a need to mitigate failure/reject rates – specifically glass particulates and optimizing the vial and the filling process.
- One of the challenges experienced in the area of capacity is, when using CMOs (which varies in size and magnitude of your business), ensuring fill slots are available. This is important especially for products in the early stages of their “robustness journey.” Small volume fills, and last minute production schedule changes on the part of the drug substance manufacturer, wreaks havoc for the CMO and the DS [drug substance] manufacturer.
Top 3 Challenges Revealed
What do we learn from these initial responses?
First, it’s apparent finding and booking the right Capacity for fill finish services is a challenge.
Second is the uncertainty around Annex 1. In December 2017, the EMA published “long-awaited” revisions, as described by GMP News, to guidelines for the "Manufacture of Sterile Medicinal Products" guidance, with public comment on those revisions having ended this past January. “The guideline published in 1971 had last been revised in parts in 2008. The present draft is the first complete revision of the guideline. Amongst other things, it was designed to pay credit to new issues like quality risk management as well as new technologies and procedures … While Annex 1 consisted of 16 pages since its last revision in 2008, the new document with its additions and changes now amounts to 50 pages…”
Third, and more tactically, shall we say, was concern about the continued reliance on visual inspection, as well as overall frustrations with analytical and testing. More automation, broader services capabilities, and much quicker turnaround are some of the needs here.
Thanks to the board for getting us started. Perhaps readers will add to this discussion. We’ve got more digging to do on both the client and provider sides to learn how we can improve fill finish outsourcing.