Biologics Fill-Finish: Technical and Operational Aspects of Tech Transfer and Scale-Up

The transfer and scale-up of a biologics fill-finish process from early-stage development to clinical manufacturing is a critical bridge in drug development. Biologics, such as monoclonal antibodies, recombinant proteins, and cell and gene therapies, are highly sensitive to environmental stresses, including agitation and friction, temperature, and material contact. Successful tech transfer ensures product quality, safety, and efficacy while transitioning from bench-scale operations to cGMP-compliant manufacturing lines.

Expertise that ensures product quality, compliance, and scalability is essential for today’s complex biologics. Alcami, a global contract development and manufacturing organization headquartered in North Carolina, offers sterile fill finish manufacturing services for liquid and lyophilized injectable drugs from preclinical development to commercial launch. Alcami’s facilities in Charleston, SC and Research Triangle Park, NC are equipped to handle complex drug products, including suspensions, emulsions, and controlled substances. 

Madhu Shaik, Executive Director-Formulation Development at Alcami, shares insight on the technical and operational aspects for the transfer and scale-up of biologics fill-finish from early-stage development to manufacturing of Phase I/II/III clinical batches.

Contract Pharma: How do you handle scale up for clinical line setups and commercial scale lines, how do they differ?

Madhu Shaik: At Alcami, clinical and commercial products are often manufactured on the same qualified equipment and on the same manufacturing lines. The line setups follow the same process for both clinical and commercial products. At Alcami, the distinction between clinical and commercial manufacturing is less about dedicated equipment and more about the maturity of the process.

Early clinical programs may rely heavily on engineering data, platform knowledge, equipment qualification, media fills, filter supplier validation data, established sterilization qualifications and line speeds, while commercial programs are supported by more extensive product-specific process characterization and validation. As product knowledge increases, process controls and operating ranges become more refined to support routine commercial manufacturing.

Contract Pharma: What is the lyophilization scale-up process?

Madhu Shaik: Our scale-up process for lyophilization relies on the development knowledge gained at the laboratory scale lyophilizer and our experience with our production scale GMP lyophilizers. Our lab scale and production scale lyophilizers are from the same vendor. Accordingly, their functional design specifications are comparable based on the lyophilizer size and capacity. We characterize the prelyophilized solution for thermal characteristics by differential scanning electron microscopy and freeze-drying microscopy which helps in understanding the collapse temperature of the formulation. This is critical to developing lyophilization cycle in the lab scale lyophilizer and to the scale-up in the production lyophilizer. 

Estimation of vial heat transfer coefficient (Kv), resistance of the dried product layer (Rp)  and sublimation rate (dm/dt) by Auto MTM cycle feature in the lab scale lyophilizer helps in understanding the safety margin associated with maximum sublimation rate in the scale-up process. An estimate of the primary cycle end point may be made using the equation for Rp reported in the literature. With the developmental knowledge gained in the lab scale lyophilizer, the theoretical estimate of the drying time will be used as input parameters for the scale-up process. In addition, the pressure difference between Pirani and Capacitance Manometer to a predetermined limit is used to determine the primary drying end point in the first scale-up engineering batch, in some cases. Based on analytical test results on the engineering batch, the cycle may be refined if necessary. 

Contract Pharma: Are there challenges around product accountability and yield optimization? If so, how can they be addressed?

Madhu Shaik: In general, product accountability is not a challenge, if the documentation captures the yield and process losses, accurately. We have not faced the accountability associated challenge.

Product yields can be optimized by reducing or eliminating product loss in the manufacturing process. For fill-finish operations of biologics, this is critical to minimize product loss as much as possible.  For example, inappropriate selection of filter surface area and filtration assembly might result in excessive retention of the product (unfiltered and filtered product), which will lead to yield loss. Process characterization/evaluation through engineering batch will help to establish the filling parameters to maintain the fill uniformity, avoiding excessive set-up yield loss. Engineering controls in the manufacturing operations help to minimize yield loss by reducing the defects in the inspection process.

Contract Pharma: What are common formulation challenges and how do you manage them?

Madhu Shaik: The formulation challenges we face are mostly in early development projects. These are generally for; (a) For insoluble/moderately soluble drugs, delivering the right dose of drug in the targeted volume for the intended route of administration, (b) Optimal buffer and pH for the stability and solubility of the drug, (c) Excipient selection for product stability, (d) viscosity optimization for drug delivery systems (e) viscosity lowering for protein therapeutics, (f) Inhibition of aggregation for peptide and protein molecules and (g) optimization of prelyophilzied solution composition for both solution and lyophilized drug product stability.

For each formulation challenge, we collaborate with our clients to design and conduct laboratory experiments that address the issue or mitigate formulation risk. Preformulation studies are conducted to evaluate the solution stability, the effect of excipients on viscosity and inhibition of aggregation for peptide and protein molecules.

Contract Pharma: What are the process evaluation studies conducted in the laboratory for transfer to manufacturing lines?

Madhu Shaik: We conduct mixing studies using single use disposable bags in our single use mixing system to evaluate the effect of mixing process at various speeds and times for both excipients and actives. If the process requires compounding at refrigerated temperature, or at elevated temperature, the process will be simulated in the formulation development laboratory to evaluate the effect of temperature on the manufacturing process and product quality. 

The filterability of the formulations is assessed at ambient room temperature and if required at refrigerated temperature using filter sizing experiments (Vmax/Pmax). The filtration process is simulated using the same type of peristaltic pump, transfer tubing and filtration assembly into the surge bag with fill needle assembly, as used in the manufacturing process. The filling process is conducted at various pump speeds to evaluate the tendency for splashing, foaming, and fill weight uniformity. PUPSIT flush studies are conducted in the laboratory to determine the volume of the drug product required to flush the PUPSIT assembly.

The material compatibility of the drug product is assessed with the process components connected from the compounding bag through the filtration assembly to the surge bag with filling needle assembly for static, intermittent or continuous flow for the proposed duration of contact time expected in the manufacturing process.

For biological drug substances, the effect of thawing and shear on product quality are evaluated. Fill interruption studies are conducted in the laboratory to simulate the effect of fill interruption on the potential for needle clogging, fill weight uniformity and quality attributes.

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