Challenges for Compound and Small-Batch Aseptic Manufacturing

Pharmaceutical manufacturers must adhere to cGMP no matter what their batch size, but producing small batches in aseptic fill/finish has particular challenges. Pharmaceutical Technology spoke with Robert Popilock, Packaging and Production segment manager for DWK Life Sciences, about some of these challenges and possible solutions using ready-to-use components.

Small-batch fill/finish

PharmTech: What are some of the considerations and challenges for fill/finish and packaging that are specific to small-batch manufacturing? 

Popilock (DWK): For small batch entities, the most notable considerations are related to capital investment (processing equipment and physical plant space), internal competency development (standards interpretation, process implementation, maintenance, and review), workflow or production capacity (hand filling, semi-automated, or high-speed lines), and meeting regulatory guidelines.

Common ways to produce an aseptic drug include internal preparation of sterile components or procurement of sterile components. The selection of one method over the other is often based on production run rates, batch frequency, and operational constraints. Small batch entities are typically constrained to plant space, capital investment, and personnel competencies. Small batch processors may be limited in their ability to dedicate space for automated cleanroom operations with high-efficiency particulate air (HEPA) environments. They may also have limited ability to make the capital and process investments to achieve United States Pharmacopeia (USP) <788> (particles), USP <85> (endotoxin) and USP <71> (sterility) (1–3) as well as environmental monitoring requirements. Of interest, the capital outlay for equipment to wash, autoclave, and irradiate can exceed $1 million, and required process verifications and content integrity evaluations can be time consuming.

To overcome these economy-of-scale limitations, small batch manufacturers seek alternatives to in-house processing by procuring or contracting components and processing services or through the use of ready-to-use  components or kits.

Although the option of procuring components and processing services does allow the small batch operator to select foundational packaging components, such as clear and amber vials, aluminum seals, and stoppers, this option is associated with operational and capital investment challenges. One limiting factor is that the required production demand may be below the minimum order quantity threshold of both the component manufacturer and processing agency. Another challenge is related to the lead time and fulfillment cycle for processing services, which can create forecasting and planning challenges for ad hoc and small batch consumption scenarios.Unplanned demand is typical, as small batch processors desire to minimize on-hand stock of processed products given that the products have a finite shelf life and desire to reduce capital deployed.  Together, such issues have driven interest in ready-to-use (RtU) packaging components.  

RtU component packs from DWK are available in quantities from 200–230 units and accompanied by a certificate of analysis (CoA) supporting off-the-shelf use. The small quantity packs consisting of clear or amber vials, aluminum seals, lyophilization stoppers, coated stoppers, and straight plus stoppers help to reduce scrap and management of opened sterile inventory and are ideally suited for small batch and compounding entities. RtU configurations consist of inventory-matched vials, stoppers, and seals available in off-the-shelf kitted quantities from 200–1200 units. The kits minimize risks associated with inventory shortages by assuring matched quantities of sterile components being available in a single kit and limit scrap through small batch pack formats.

As can be seen, small batch manufacturers can match their batch rates, batch frequency, and operational preferences or governances to maximize workflow, investment, and risk. 

Compounding pharmacies

PharmTech: What challenges do you see in fill/finish at compounding pharmacies? 

Popilock (DWK): Compound pharmacies create medications tailored to the specific needs of the patient by combining and mixing ingredients, then packaging them for delivery and use. Typically compounding is a small batch or ad hoc [as needed] production scenario. While compounding is becoming increasingly common, there is a large portion of compounders who may struggle to comply with regulations, including the demonstration of consistent production of clean and sterile parenteral packaging components. Despite the fact that there are guidelines for industry and sterile drug products that require conformance to aseptic processing (cGMP) and USP <797> Pharmaceutical Compounding-Sterile Preparations (4), ongoing problems have led to intensified efforts by FDA to assure safety of compounded drug products. 

In addition to regulatory compliance, compounders who use sterile vials and closures are also challenged by physical plant space to host sterile processing equipment, capital investment in expensive washing and sterilization equipment, and analytical capabilities to assure compliance to published standards, along with personnel required to implement, maintain, and audit processes and procedures to assure compliance. Like fill/finish operations, compounders are challenged in coordinating the purchase of raw components and contracting processing services at minimum order quantities. They also face challenges associated with navigating the processor’s schedule and processing backlogs. This makes RtU solutions a viable alternative through off-the-shelf and small pack quantities accompanied with CoA and traceability documentation. 

The regulatory environment can be quite complex. So much so, that we are seeing a trend in the number of manufacturing projects being outsourced for large batches to contract manufacturing organizations (CMOs). CMOs typically have dedicated staff who perform such compliance activities and are extremely efficient and less prone to complications that may delay production. In the case of small batch manufacturing and compounding entities, however, their volumes don’t align with such outsourcing agencies, so they must rely on their own compliance person. Knowledge of particulate cleaning, final water for injection rinse, total organic carbon levels, depyrogenation, autoclaving, irradiation, surface treatments, sterile bagging methods, CoA handling, and keeping up with compliance standards pose obvious challenges. A common misconception is that RtU components and kits are associated with a cost premium. However, when balancing against non-compliance risks, adding regulatory headcount, and annual training and processor audits, the convenience of filing the CoA becomes desirable.

References

1. USP, USP <788> “Particulate Matter in Injections” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012 ).
2. USP, USP <85> “Bacterial Endotoxins Test” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012 ).
3. USP, USP <71> “Sterility Tests” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012).
4. USP, USP <797> "Pharmaceutical Compounding-Sterile Preparations" (US Pharmacopeial Convention, Rockville, MD, 2008).