Pharma Fundamentals: Biologics Development and PDA’s Technical Report No. 56

In this episode of PharmTech’s Pharma Fundamentals, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates and a member of PharmTech’s editorial advisory board, and Amnon Eylath, president and founder of Broad Spectrum GXP, discuss biologics development, the quality system, and the Parenteral Drug Association’s (PDA) revision to Technical Report No. 56 (TR56),¹ which Eylath is a co-author on.

 

Link to the Video and Article on Pharmaceutical Technology

 

Why a Separate Framework Was Needed

The PDA’s TR56, Application of Phase-Appropriate Quality Systems and Good Manufacturing Practice to the Development of Biological Product Drug Substance, was written in response to a practical problem: companies were applying full commercial-scale quality standards to early-phase clinical products, which wasn’t working. Certain systems simply cannot and should not, according to Eylath, be in place during early development. The report, now in its third version, provides guidance on scaling quality requirements appropriately across development phases. The report’s core principles apply broadly across both biologics and small molecules; however, the differences between its application to biologics compared with small molecules lie in complexity and in the relative level of containment and contamination control required. In addition, FDA requested that TR 56 (2012) also serve as a guide to best practices for smaller and academic biologic manufacturers who may not have the level of experience to understand what must be in place throughout the development of a biological drug substance.

 

Where the Two Paths Diverge: Microbiology and Containment

The most significant practical difference between a biologics quality system and a small-molecule quality system is the degree of rigor required around microbiology, sterility, and containment, according to Eylath. Small-molecule manufacturing focuses more on cleanliness and sanitary conditions (eliminating factors such as gross microbial or fungal contamination, insects, rodents, particulates, and chemical contamination), but once a process is proven to destroy microorganisms, or a formulated product is verified to be bacteriostatic, to contain effective preservatives, or to be too dry to support bacterial growth, routine microbiological testing can be reduced.

 

Biologics are different because they are produced using living cells, bacterial or eukaryotic, and the cell culture and fermentation process itself introduces and relies on those living organisms. Because of this, the manufacturing environment cannot be technically described as “sterile,” a term that indicates the validated absence of all viable microorganisms, demonstrated to a specified sterility assurance level. The standard applied to biologics instead is “low bioburden”: a defined, controlled, and acceptably low level of non-objectionable organisms, with organisms that are objectionable (not native to the intended culture and posing a safety or quality risk) excluded entirely. In practice, the two standards converge on the same intended outcome, eliminating risk-bearing contamination, but they differ in regulatory definition and acceptance criteria. Any objectionable microbial contamination (environmental bacteria and spores, Escherichia coli, fungi, and similar organisms) threatens patient safety and product quality. This risk requires rigorous, continuous environmental, containment, and bioburden controls throughout the entire biologics manufacturing process.

 

Process Fragility and Time Pressure

Biological drug substances are inherently more fragile than small molecules. Small-molecule intermediates can often be crystallized and held in a stable solid state for extended periods at room temperature or under refrigeration. Biologic intermediates frequently cannot be crystallized, and when they can be held at all, they often require ultra-low temperature, frozen storage, and only for a limited window, explains Eylath. A drug substance collected from a bioreactor may need to advance to the next manufacturing step or to lyophilization within 3 to 7 days, sometimes with product shipping across borders included in that window.

 

Because of this time sensitivity, contamination-mitigating design, technology, and procedures must be implemented before manufacturing begins. Rapid, yet high-quality investigations must be conducted in the event of deviations or unallowable excursions to the process described above. In small-molecule development, a manufacturing hold pending investigation is inconvenient; in biologics, it may mean losing the batch entirely, which can in turn create a supply shortage of the final drug product. Quality teams need to make quick, risk-based and science-based decisions that include subject matter expert involvement. Therefore, while the investigative methodology is the same as for small molecules, the timeline for reaching root cause is usually dramatically compressed for biologics, says Eylath.

 

Container Closure and Extractables/Leachables

Container closure concerns, particularly extractables and leachables, are more prevalent for biologics and for injectable small-molecule drugs, and should be addressed in both the quality system and in facility and process design. For sterile injectable products, whether biologic or small molecule, container closure compatibility is a critical quality attribute. Whether the product is in a glass vial, plastic vial, or prefilled syringe, the components (e.g., stopper, plunger seal, silicone coating) must be tested for extractables and leachables.

 

The mechanism of concern differs by modality. Biologics formulations are often pH-sensitive or contain surfactants, which can actively extract materials from container components. Small molecules, depending on their own formulation chemistry (for example, organic solvents or reactive functional groups), can instead have intrinsic chemical reactivity that attacks the container or closure drug-facing surface. Vendor data provide a useful starting point, but product-specific testing is required, because a leachable that is acceptable in one formulation may degrade or contaminate another.

 

The Quality System Framework: More Similar Than Different

At the systems level (policies, standard operating procedures, risk assessments, documentation practices, knowledge transfer), a biologics quality system is similar to one for small molecules. TR56 emphasizes that the governing quality infrastructure should be the same; what changes is what is being governed. Eylath explains that this version strengthens guidance around risk assessment and knowledge transfer starting as early as the research phase and continuing through pre-GMP manufacturing development and scale-up, recognizing that tacit knowledge lost during phase transitions is a leading cause of both early and later-stage failures across both modalities.

 

While biologics demand professionals with deeper biological science fluency, faster decision-making cycles, and stricter microbiological controls, the quality system architecture itself remains fundamentally consistent with small-molecule best practices.The PDA’s TR56, Application of Phase-Appropriate Quality Systems and Good Manufacturing Practice to the Development of Biological Product Drug Substance, was written in response to a practical problem: companies were applying full commercial-scale quality standards to early-phase clinical products, which wasn’t working. Certain systems simply cannot and should not, according to Eylath, be in place during early development. The report, now in its third revision, provides guidance on scaling quality requirements appropriately across development phases. The report’s core principles apply broadly across both biologics and small molecules; however, the differences between its application to biologics compared with small molecules lie in complexity.

 

Reference

Brewer RA, Eylath AA, Kirschbaum N, et al. Technical Report No. 56 (Revised 2026): Application of Phase-Appropriate Quality Systems and Good Manufacturing Practice to the Development of Biological Product Drug Substance. PDA. February 2026. https://www.pda.org/bookstore/product-detail/8742-technical-report-no-56-revised-2026