With proliferating modalities entering and moving through the biopharmaceutical industry’s development pipeline, drug presentations are expanding and diversifying to accommodate. Even “traditional” biologics such as monoclonal antibodies (MAbs) have evolved in their formulation and packaging, with the emergence of highly concentrated drug products, prefilled syringes, and devices that enable patients to inject themselves at home rather than visiting a local clinic for drug infusion. Patients, clinicians, and payers are demanding convenience and cost-effectiveness as well as safety, quality, and efficacy from their medications — and compliance with treatment regimens improves with easier administration options.
All of those developments are changing the work of formulators and fill–finish operators at many biopharmaceutical companies, and changes often can introduce risk when it comes to regulatory compliance and quality systems. Discussions of such risks were prevalent throughout the final years of the Institute of Validation Technology’s (IVT’s) open-source Journal of Validation and Journal of GXP Compliance before they were discontinued in 2022. Since then, BPI has absorbed much of their contents. In fact, the regular issue accompanying this special insert includes two articles from contributors we met through IVT. One of those reports highlights the risks involved in retraining regimens for employees (e.g., fill–finish operators) who fail in their initial assessments for conforming to new standard operating procedures (SOPs) (1).
A number of recent IVT articles now hosted on the BPI website are worth the attention of readers who work in aseptic processing. BPI editorial advisor Tim Sandle, for example, has been prolific in his discussions of aseptic processing and related concerns (2, 3). In a late-2021 article, he outlined essential elements of contamination control strategy (CCS): manufacturing control based on product type, demand, process, and risk; control of critical quality attributes to meet regulatory requirements; and cross-contamination control based on requirements for containment and product segregation (2). Contamination and its sources, he writes, can include microorganisms and their by-products (e.g., endotoxins), chemicals, pests, visible and subvisible particles, and residues from cleaning solutions and other product streams.
Why have a contamination control strategy? The answer is not simply to stay ahead of the regulatory curve (important though this is), but also to gain product and process knowledge, drawing on sound science, to seek the optimal improvements and controls over each stage of purchasing, manufacturing, and product distribution. Through this, products and patients can be best protected. (2)
Sandle emphasizes the “control” aspect and measures taken to achieve it. They should be based on quality risk management within the quality by design (QbD) paradigm, using technical measures based on science and knowledge. Organizational control measures are part of pharmaceutical quality systems and include procedural controls (through SOPs) that take human factors into consideration. A continuing process beginning with requirements analysis informs design and implementation of a control strategy, which provides a basis for testing and data trending going forward. As new technologies are implemented, control strategies must evolve through periodic review of changing requirements, thus beginning a new iteration of the process.
CCS is important especially in aseptic manufacturing, where the objective is sterility assurance for drug products. Sandle writes, “The imperative is to prevent microbial ingress” (2). He describes sterility assurance as “a holistic concept” that must protect both drug substance and drug product from contamination at all stages of manufacturing, “from in-coming raw materials through to finished products.” In addition to the details of aseptic processing itself, control measures include design and operation of facilities/cleanrooms and utilities; definition of process, material, and personnel flows; validation of environmental monitoring and cleaning/sterilization procedures; and personnel training and qualification.
Sandle points out that outsourcing can introduce additional risks, especially without adequate planning in technology transfer. Incomplete process validation and changing specifications can complicate outsourced projects as well. Project managers need to remember that regulators expect the sponsor of a product to be responsible for its quality, safety, and efficacy — rather than leaving them up to contract service providers to control.
Visual Inspection: Sandle narrowed in on a specific aspect of contamination control in an early 2022 article (3): “Regulators require pharmaceutical products that are injected into the human body (which are by inference sterile products) to be free of visible particulates.” Minimizing the potential for particulate contamination includes testing based on visual inspection as part of batch release and for stability and other retained samples. Detected particles must be identified, investigated, and subject to corrective and preventative actions (CAPAs).
The process of close visual inspection of pharmaceutical products is an important part of pharmaceutical quality control, and it is necessary to safeguard patient safety so that products with visible particulates are not released into the market. Operators performing visual inspections must be appropriately trained, supported by well-written operating procedures, and be able to differentiate visible particles of different sizes, colors, and dimensions. The training process needs to be supported by eye tests. (3)
The article includes a useful comparison of international standards and regulations covering such training and testing, and it details the different types of testing involved.
Warning Letters: In a 2020 article, Jeanne Moldenhauer (chief science officer at Excellent Pharma Consulting) pointed out the importance of warning letters from US Food and Drug Administration (FDA) inspectors — not only to the companies receiving them, but also to others for which they serve as case studies to learn from. She offered as an example “two different warning letters to the Akorn pharmaceutical company in 2019” (4).
Both warning letters had significant issues with aseptic processing and other quality systems. It’s never a good idea to be a company with two warning letters in the same year. Most companies do not want even a single warning letter. It is even worse to know about the warning letters and not look at whether these same situations occur within your own facility. There is much that can be learned from the hard lessons of others. Warning letters provide a good deal of information on the issues of concern to FDA and can aid in the preparation for an inspection at your site. (4)
In that particular case, Moldenhauer pointed out, employees “displayed poor aseptic practices during aseptic set-up and filling operations,” such as failing to sanitize their hands or disinfect stopper bags. Media-fill simulation exercises were inadequate, and cleanroom designs were deficient. The environmental monitoring program was reportedly deficient, as was the cleaning program. Even more surprising was the fact that no stability studies had been performed for a given product, and the company had no test method validated for doing so. The inspectors expressed concern over the company’s out-of-specification (OoS) investigations, stating that they did not support scientifically sound conclusions and that CAPAs were not timely. “Numerous investigations were open for more than six months. Some were open for more than a year.” Batch records and laboratory investigations both were incomplete. Computer-system controls arose as a problem, which is familiar to people who follow published warning letters. And the company’s response to previous warning letters was deemed to be insufficient.
FDA warning letters are made publicly available online at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters.
Convenience Kits and Copackaging: A drug and medical device come as individual constituent parts in the same package. Examples include product vials packaged with delivery devices or accessory kits (empty syringes, autoinjectors, and transfer sets).
Prefilled Drug or Biologic Delivery Devices: A chemical drug or biological product is filled into or otherwise combined with a medical device for the sole purpose of
Devices Coated, Impregnated, or Otherwise Combined with a Drug or Biologic: These medical devices serve a purpose in addition to delivering a drug. For example, pillscan be embedded with sensors; contact lenses, catheters, and sutures can be drug-coated; stents and leads can elute drugs when in place, condoms can include spermicide, dental floss can include fluoride, and bone cements can include antibiotics. Biologic examples include live cells seeded on or in a device scaffold and extracorporeal columns with bound proteins.
Drug–Biologic Combinations: These combination products include antibody–drug conjugates (ADCs) and progenitor cells that are combined with drugs to promote their targeting within a recipient’s body.
Cross-Labeled but Separate Products: Some lightactivated drugs and biologics might not be copackaged with a specific light-source device but are labeled to require use with it.
Other Combination Products: A drug, device, and biologic could be combined into a single product, such as a prefilled syringe containing an ADC or a kitted device for
Containers and Devices: In a 2022 article, Paul Pluta (adjunct associate professor at the University of Illinois at Chicago’s College of Pharmacy) and Alan Mancini (director of pharmaceutical technology at Watson Laboratories) presented a few more case studies, these featuring primary containers of drug products and company responses to identified problems (5). No regulatory intervention was necessary in these cases.
Pharmaceutical containers generally are considered to be nonreactive and inert, but some can be problematic under certain conditions such as in the presence of specific formulation ingredients. Compliance professionals must consider the potential for interactions between drug products and their containers when investigating technical problems. The authors advise readers to “look beyond the obvious when conducting compliance investigations” (5). In most of the case studies described, initial speculation about the causes of trouble turned out to be wrong.
Also vital in problem-solving was team competence and people with appropriate expertise, skill sets, and education. Team members include internal and external personnel — e.g., vendor representatives for container suppliers. Internal people must evaluate problems, understand the limitations of their capabilities, and involve representatives with appropriate expertise and capabilities from external sources. (5)
In a 2020 article, Richard Poska (managing director of regulatory affairs, chemistry, manufacturing, and controls at Flexo LLC) highlighted issues with reliability of a specific type of container (6). Emergency-use injectors face many similar concerns to those of other combination products for drug delivery, and the FDA has provided specific guidance documents for companies developing them (7–9). The “Combination-Product Categories” box lists several types of such technologies, which are expanding as an increasingly important crossover segment of the pharmaceutical and device industries.
Combination-product regulatory submissions should include information to verify and validate that injectors meet reliability specifications, which the agency considers to be acceptable when they specify reliability of 99.999% with a 95% confidence level. A reliability report should cover input/output design considerations in the development of an injector device. Poska highlights the usefulness of fault-tree analysis for identifying critical performance attributes and setting meaningful specifications over a broad range of product exposure conditions. These concepts can be applied to postapproval changes made for improving injector reliability as well as in development of new products. In fact, the FDA emphasizes monitoring and improving reliability as part of each such product’s life cycle.
On the Following Pages
Contributors to this featured report include a consultant, an academic researcher, and a science executive with a commercial laboratory. They cover an array of topics under the formulation/fill–finish theme.
First, Patrick Nieuwenhuizen (PharmaLex) reports from a September 2022 meeting on the recently revised EU good manufacturing practice guide’s Annex 1. This was the third of four events organized by the Parenteral Drug Association (PDA) to provide a forum for industry and regulators to discuss the recent Annex 1 regulation revision, and it was the first such event to take place after the annex was finalized. Topics covered included implementation of the new regulation, quality risk management, CCS, preuse poststerilization integrity testing, container–closure integrity testing, and facilities and barrier systems for aseptic processing.
Next, BPI managing editor Brian Gazaille speaks with Robert O. Williams III (University of Texas at Austin) about applications of thin-film freeze-drying in producing dry-powder formulations of MAbs for inhaled delivery. Historically, MAb products have been formulated as liquid suspensions for infusion or injection. Now, branching off of successes among inhalable vaccine products, researchers such as Williams and his team are making significant progress in establishing equipment for dry-powder MAb formulation. He explains how liquid formulation and lyophilization can compromise biologic quality and why the biopharmaceutical industry has yet to develop commercially viable processes for manufacturing inhalable MAb products. Then he describes how thin-film freeze-drying works, how it surpasses limitations associated with traditional lyophilization methods, and how his laboratory is leveraging machine learning to predict the aerosol properties of formulated drug products.
Finally, Gazaille talks with Eric Woods (Ossium Health) about formulating cell therapies for cryopreservation and clinical use. The size and complexity of living cells raise distinctive hurdles during drug-product cryopreservation — even if such products are processed, frozen, and thawed in much smaller batch sizes than are drugs based on MAbs and other proteins. In this second half of a discussion that began in BPI’s November 2022 eBook, Woods addresses cryopreservation requirements for hematopoietic stem cells. Whereas part 1 featured considerations for recovering such cells from the bone marrow of deceased donors, this installment focuses on industry needs for effective cryoprotectants, freeze–thaw protocols, and operator training.
1 Jaiganesh V, Ioakeim M, Gangadhar S. Learning Management: Evaluation of Retraining Risk at Indian Pharmaceutical Companies. BioProcess Int. 21(3) 2023: 16–23.
2 Sandle T. Anatomy of a Contamination Control Strategy for Sterile Manufacturing. J. GXP Compliance 25(2) 2021; https://bpi.bioprocessintl.com/hubfs/IVT%20-%20GXP%20Archive/3-21-Anatomy%20of%20Contamination%20Control%20-%20sandle-1.pdf.
3 Sandle T. What the Eye Can See: Vision Requirements for Personnel Who Inspect Injectable Pharmaceuticals. J. GXP Compliance 26(1) 2022; https://bpi.bioprocessintl.com/hubfs/IVT%20-%20GXP%20Archive/1-22-What%20the%20eye%20can%20see-1.pdf.
4 Moldenhauer J. Regulatory Actions Taken in Response to Issues in Aseptic Processing and the Quality System. J. GXP Compliance 24(1) 2020; https://bpi.bioprocessintl.com/hubfs/IVT%20-%20GXP%20Archive/1-2020-%20IVT%20Network%20-%20Regulatory%20Actions%20Taken%20in%20Response%20to%20Issues%20in%20Aseptic%20Processing%20and%20The%20Quality%20System%20-%202020-01-28.pdf.
5 Pluta PL, Mancini AM. Compliance Case Study #19: Primary Container Problems. J. GXP Compliance 26(1) 2022; https://bpi.bioprocessintl.com/hubfs/IVT%20-%20GXP%20Archive/1-22-Comp%20CASE%20STUDY%2019%20Container%20Problems%20.pdf.
6 Poska R. Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors: A Review of Draft FDA Guidance for Industry. J. GXP Compliance 24(3) 2020; https://bpi.bioprocessintl.com/hubfs/IVT%20-%20GXP%20Archive/5-20-IVT%20Network%20-%20Technical%20Considerations%20For%20Demonstrating%20Reliability%20Of%20Emergency-Use%20Injectors%20A%20Review%20Of%20Draft%20FDA%20Guidance%20For%20Industry%20-%202021-11-02.pdf.
7 CBER/CDER/CDRH. Guidance for Industry: Technical Considerations for Pen, Jet, and Related Injectors for Use with Drugs and Biologics Products. US Food and Drug Administration: Rockville, MD, July 2013; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products.
8 CBER/CDER/CDRH. Draft Guidance for Industry: Technical Considerations for Demonstrating the Reliability of Emergency-Use Injectors Submitted Under a BLA, NDA, or ANDA. US Food and Drug Administration: Rockville, MD, April 2020; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-considerations-pen-jet-and-related-injectors-intended-use-drugs-and-biological-products.
9 CBER/CDER/CDRH/ORA. Guidance for Industry: Current Good Manufacturing Practice Requirements for Combination Products. US Food and Drug Administration: Rockville, MD, January 2017; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-requirements-combination-products.