Evaluation of Packaging Materials in Freeze-Drying: Use of Polymer Caps and Nested Vials and Their Impact on Process and Product Attributes.

Current trends in the pharmaceutical industry led to a demand for more flexible manufacturing processes with smaller batch sizes. Prepackaged nested vials that can be processed as a unit were introduced into the market to fulfill this need. However, vial nests provide a different thermal environment for the vials compared to a hexagonal packaging array and could therefore influence product temperature profiles, primary drying times, and product quality attributes. Polymer caps with the possibility of vial closure inside the freeze-drying chamber were developed to remove the risks and need of a crimping process. A general concern with the use of such caps is the possibility of an increase in resistance to water vapor flow out of the vial. This case study investigated the effect of the LyoSeal® and PLASCAP® polymer caps and EZ-fill® nests on the freeze-drying process. Amorphous and partially crystalline model formulations were freeze-dried. Process data and product quality attributes were compared for regularly stoppered vials and vials with polymer caps as well as vials in a hexagonal packaging array and nested vials. The results indicated no increased resistance or impeded water vapor flow by the polymer caps. Differences in the macro- and microscopic appearances of products and a trend towards lower product temperatures were observed for the investigated nest type compared to a regular hexagonal packaging array. Consequently, the polymer caps could be used as an alternative to regular stoppers without affecting freeze-drying process data or product quality attributes, while the different thermal environment of nested vials should be considered.

Preventing Cross-Contamination during Lyophilization: GMP and Occupational Cleaning Requirements for Nonproduct and Indirect Product-Contact Parts.

A detailed overview is provided for the possible patient exposure to highly potent active pharmaceutical ingredients (HPAPIs) from potential cross-contamination through the lyophilization process. The intent of this paper is to raise awareness of the risk(s) to patients and stimulate the implementation of adequate risk-based controls, such as containment process(es), use of adequate surrogates in cleaning validation/verification, and test method-sensitivity-based cleaning validation acceptance conditions. Although lyophilizers are considered to be nonproduct-contact surfaces because their surfaces and fixtures do not usually come into direct contact with the product, product contamination can occur at critical locations within a lyophilizer and/or during the unloading process. Contamination of the air because of released product particles can also create a risk. Therefore, special attention should be paid to HPAPIs, as the permitted daily exposures (PDEs) for patients are particularly low. During a lyophilizer cycle, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Specific considerations for contamination containment for the lyophilizer unloading process are presented. Suggestions are provided for the prevention of patient exposure through cross-contamination via direct-contact areas and prevention of manufacturing personnel exposure via non-direct-contact areas. A surface limit(s) of 1 PDE per square decimeter for nonproduct-contact surfaces inside a lyophilizer is proposed. Risk-based cleaning validation/verification strategies are discussed, with specific consideration of the quality control test method sensitivity expectations and use of suitable surrogates for lyophilized products in the cleaning verification studies.LAY ABSTRACT: This paper provides an overview of important points to consider during the manufacture of highly potent active pharmaceutical ingredients (HPAPI) with the intention to limit patient exposure and/or manufacturing personnel exposure to these highly toxic HPAPIs. HPAPI can potentially be spread during the freeze-drying process (lyophilization) and may cross-contaminate products. Manufacturing personnel and patients taking other freeze-dried products made in the same lyophilizer could be contaminated. It is therefore necessary to implement rigorous contamination controls. Within the lyophilizer, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Cleaning validation/verification studies, intended to demonstrate sufficient cleanability of the freeze-drying process as well as the recommended test method sensitivity to detect these highly toxic HPAPIs, are reviewed. Limits for the relevant production surface areas where cross-contamination and/or personnel exposure (through direct contact) could occur are proposed in this paper.

Process analytical technology (PAT) for biopharmaceutical products: Part II. Concepts and applications.

Implementing real-time product quality control meets one or both of the key goals outlined in FDA's PAT guidance: "variability is managed by the process" and "product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions." The first part of the paper presented an overview of PAT concepts and applications in the areas of upstream and downstream processing. In this second part, we present principles and case studies to illustrate implementation of PAT for drug product manufacturing, rapid microbiology, and chemometrics. We further present our thoughts on how PAT will be applied to biotech processes going forward. The role of PAT as an enabling component of the Quality by Design framework is highlighted. Integration of PAT with the principles stated in the ICH Q8, Q9, and Q10 guidance documents is also discussed.

Semiautomated inspection versus fully automated inspection of lyophilized products.

The development of fully automated inspection systems for parenteral products has created a situation of high expectations regarding productivity and quality improvements. However, not all products and production situations are suited for automation. A guideline for inspection and automation strategies will be discussed, structuring the field of lyophilized products according to the critical decision parameters.