Showing papers in "Pda Journal of Pharmaceutical Science and Technology in 2018"

Impact of Stainless Steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation

Abstract: Rapid oxidation of polysorbate 80 in histidine buffer was observed upon brief exposure to stainless steel. Liquid chromatography-mass spectrometry analysis indicates degradation of both polyoxyethylene sorbitan and polyoxyethylene head groups and unsaturated fatty acid chains, with further confirmation by reversed-phase high-performance liquid chromatography data. Both Fe2+ and Fe3+ were shown to induce polysorbate 80 oxidation. The degree of oxidation in polysorbate 20 and polysorbate 80 are comparable for the head groups and saturated fatty acid esters. However, the same phenomenon was not observed with placebo or monoclonal antibody at a threshold protein concentration, formulated in sodium citrate, in combination with histidine and sodium citrate, or with Na2 ethylenediaminetetraacetic acid (EDTA). Further, polysorbate 80 oxidation was not observed with Lilly's antibody containing the active ingredient LY2951742, at or above a threshold concentration. Finally, no major polysorbate 80 degradation was observed in histidine buffer, with or without protein, in containers composed of glass or plastic, or when stainless steel exposure was otherwise completely absent. Finally, the 2-oxo oxidation form of histidine was not observed, but the other oxidation products and modifications of histidine were identified.LAY ABSTRACT: Rapid oxidation of polysorbate 80 in histidine buffer was observed upon brief exposure to stainless steel. The degree of oxidation in polysorbate 80 and polysorbate 20 were comparable. However, the same phenomenon was not observed with placebo when formulated in sodium citrate, in combination with histidine and sodium citrate, or with Na2 ethylenediaminetetraacetic acid (EDTA). Polysorbate 80 oxidation was not observed with Lilly's antibody containing the active ingredient, LY2951742, at or above a threshold concentration. No major polysorbate 80 degradation in histidine buffer was observed when stainless steel contact was completely absent.

Data Integrity: History, Issues, and Remediation of Issues.

Abstract: Data integrity is critical to regulatory compliance, and the fundamental reason for 21 CFR Part 11 published by the U.S. Food and Drug Administration (FDA). FDA published the first guideline in 1963, and since then FDA and European Union (EU) have published numerous guidelines on various topics related to data integrity for the pharmaceutical industry. Regulators wanted to make certain that industry capture accurate data during the drug development lifecycle and through commercialization-consider the number of warning letters issued lately by inspectors across the globe on data integrity. This article discusses the history of regulations put forward by various regulatory bodies, the term ALCOA Plus adopted by regulators, the impact of not following regulations, and some prevention methods by using some simple checklists, self-audit, and self-inspection techniques. FDA uses the acronym ALCOA to define its expectations of electronic data. ALCOA stands for Attributable, Legible, Contemporaneous, Original, and Accurate. ALCOA was further expanded to ALCOA Plus, and the Plus means Enduring, Available and Accessible, Complete, Consistent, Credible, and Corroborated. If we do not follow the regulations as written, then there is a huge risk. This article covers some of the risk aspects. To prevent data integrity, various solutions can be implemented such as a simple checklist for various systems, self-audit, and self-inspections. To do that we have to develop strategy, people, implement better business processes, and gain a better understanding of data lifecycle as well as technology.LAY ABSTRACT: If one does a Google search on "What is data integrity?" the first page will give the definition of data integrity, how to learn more about data integrity, the history of data integrity, risk management of data integrity, and at the top about various U.S. Food and Drug Administration (FDA) and European Union (EU) regulations. Data integrity is nothing but about accuracy of data. When someone searches Google for some words, we expect accurate results that we can rely on. The same principle applies during the drug development lifecycle. Pharmaceutical industry ensures that data entered for various steps of drug development is accurate so that we can have confidence that the drugs produced by the industry are within some parameters. The regulations put forward by FDA and EU are not new. The first regulation was published in 1963, and after that regulators published multiple guidelines. Inspectors from both regulatory bodies inspected the industry, and they found that the data was not accurate. If pharmaceutical industry produces drugs within the stated parameters, then it is approved and available in the market for patients. If inspectors find that the data is modified, then the drug is not approved. That means revenue loss for industry and drugs not available for patients. In this article, I explain some of the remediation plans for the industry that can be applied during the drug development lifecycle pathway.

Impact of Drug Formulation Variables on Silicone Oil Structure and Functionality of Prefilled Syringe System

Abstract: Use of prefilled syringes to self-administer biologics via subcutaneous administration provides convenience to patients. The barrel interior of prefilled syringes is typically coated with silicone oil for lubrication to aid plunger movement at the time of administration. This study intended to evaluate the impact of formulation variables on the silicone oil on the barrel interior surface. Characterization techniques including syringe glide force, break loose force, Schlieren imaging, contact angle, inductively coupled plasma spectrometry, and thin film interference reflectometry were used in assessing the interactions. Data indicated that formulation variables such as pH, buffer/tonicity agent type and concentration, and surfactant present in the formulation can effect silicone oil lubrication of prefilled syringes, leading to changes in functional properties of the syringe over time. Syringe samples containing acetate and histidine buffers showed an increase in glide force at accelerated storage temperature conditions, but the change was minimal at 5 °C. The samples with the highest glide force correlated with the presence of mannitol in combination with sodium acetate buffer. Sodium chloride had lesser impact on glide force than mannitol. Samples with higher glide force exhibited a substantial change in the silicone oil layer of the syringe, as observed with Schlieren imaging, as well as a significant reduction in surface hydrophobicity, as demonstrated through contact angle measurement. These data indicated that the structure of the siliconized surface can change over time in contact with different formulations. During formulation development of drug products in prefilled syringes, in addition to potential impact on molecule stability, the selection of formulation variables should also be guided by assessing the impact to syringe functionality with the glide force as one of the key parameters. LAY ABSTRACT: Self-administering drug products packaged in prefilled syringes provides convenience to patients. The interior of a prefilled glass syringe is typically lubricated with silicone oil for easy plunger movement during injection. This article discusses the impact of formulation excipients on silicone oil coating inside the syringe. Characterization techniques were used to assess the ease of plunger movement and structure of the silicone coating. Data indicate formulation excipients can affect silicone oil distribution of prefilled syringes, leading to an increase in plunger glide force at accelerated storage temperature conditions. The increase in glide force within a prefilled syringe with or without an auto-injector can have an impact on dose accuracy and user experience. Syringes with a higher plunger glide force appeared to exhibit a change over time in surface energy and structure of the silicone oil layer in contact with particular formulations.

Vapor Phase Hydrogen Peroxide Decontamination or Sanitization of an Isolator for Aseptic Filling of Monoclonal Antibody Drug Product—Hydrogen Peroxide Uptake and Impact on Protein Quality

Abstract: A monoclonal antibody drug product manufacturing process was transferred to a different production site, where aseptic filling took place within an isolator that was decontaminated (sanitized) using vapor phase hydrogen peroxide (VPHP). A quality-by-design approach was applied for study design to understand the impact of VPHP uptake on drug product quality. Both small-scale and manufacturing-scale studies were performed to evaluate the sensitivity of the monoclonal antibody to hydrogen peroxide (H2O2) and characterize VPHP uptake mechanisms in the filling process. The acceptable H2O2 uptake level was determined to be 100 ng/mL for the antibody in the H2O2 spiking study; protein oxidation was observed above this threshold. The most prominent sources of VPHP uptake were identified to be the silicone tubing assembly (associated with the peristaltic pumps) and open, filled vials. Silicone tubing, an effective depot to H2O2, absorbs VPHP during different stages of the filling process and transmits H2O2 into the drug product solution during filling interruptions. A small-scale isolator model, established to simulate manufacturing-scale conditions, was a useful tool in understanding H2O2 uptake in relation to tubing dimensions and VPHP concentration in the isolator air (or atmosphere). Although the tubing assembly had absorbed a substantial amount of VPHP during the decontamination phase, the majority of H2O2 could be removed during tubing cleaning and sterilization in the subsequent isolator aeration phase, demonstrating that H2O2 in the final drug product solution is primarily taken up from residual VPHP in the isolator during filling. Picarro sensor monitoring demonstrated that the validated VPHP aeration process generates reproducible residual VPHP profiles in isolator air, allowing small-scale studies to provide relevant recommendations on tubing size and interruption time limits for commercial manufacturing. The recommended process parameters were demonstrated to be acceptable and rendered no product quality impact in six consecutive manufacturing batches in the process validation campaign. Overall, this case study provides process development scientists and engineers an in-depth understanding of the VPHP process and a science-based approach to mitigating drug product quality impact. LAY ABSTRACT: While the use of vapor phase hydrogen peroxide as a sanitizing agent for isolator and cleanroom decontamination has gained popularity in recent years, its impact on product quality during aseptic manufacturing of biopharmaceutical drug products is yet to be fully understood. With this scope in mind, this case study offers a detailed account of defining process parameters and developing their operating ranges to ensure that the impact to product quality is minimized. Both small-scale and manufacturing-scale studies were performed to assess the sensitivity of a monoclonal antibody to hydrogen peroxide, to characterize hydrogen peroxide uptake sources and mechanisms, and to eventually define process parameters and their ranges critical for minimizing product quality impact. The approach and outcome of this study is expected to benefit scientists and engineers who develop biologic product manufacturing processes by providing a better understanding of drug product process challenges.

Real-Time PCR Detection of Burkholderia cepacia in Pharmaceutical Products Contaminated with Low Levels of Bacterial Contamination

Abstract: A real-time polymerase chain reaction (RT-PCR) assay was developed to detect Burkholderia cepacia in pharmaceutical products contaminated with low levels of bacteria. Different pharmaceutical suspensions were artificially contaminated with B. cepacia, Escherichia coli, Staphylococcus aureus, and Bacillus megaterium. After a 24 h incubation in trypticase soy broth with Tween 20, samples were streaked on mannitol salt, phenyl ethyl alcohol, eosin methylene blue, MacConkey, and pseudomonas isolation agar. Microbial DNA was extracted from each sample by using a Tris-EDTA, proteinase K, Tween 20 buffer. Regular PCR targeting the 1.5 kilobases 16S rRNA eubacterial gene and cloning showed the predominant DNA in the extracted mix belonged to E. coli. Selective media isolation of bacterial contamination showed B. cepacia only detected on pseudomonas isolation while eosin methylene blue and MacConkey detected only E. coli. RT-PCR using primers PSL1 and PSR1 amplified a 209 bp 16S rRNA fragment using a Roche LightCycler 96® system with SYBR green I, a common double-stranded binding dye. The cycle at which fluorescence from amplification exceeds the background fluorescence was referred to as quantification cycle. All samples were found to be positive by standard microbiological testing and RT-PCR. B. cepacia was detected within 30 h in all contaminated samples using RT-PCR. Based upon standard curve analysis of B. cepacia DNA, the minimum DNA concentration that could be detected was 10 fg/uL with a correlation value of 0.98. RT-PCR detection of B. cepacia allowed faster quality control analysis, corrective actions, and process optimization. LAY ABSTRACT: A real-time polymerase chain reaction (RT-PCR) assay was developed to detect Burkholderia cepacia in pharmaceutical products contaminated with low levels of bacteria. B. cepacia is the number one reason for microbial contamination recalls of non-sterile drug products in the USA. RT-PCR using primers PSL1 and PSR1 amplified a 209 bp 16S rRNA fragment using a Roche LightCycler 96® system with SYBR green I, a common double-stranded binding dye. All samples were found to be positive by standard microbiological testing and RT-PCR. B. cepacia was detected within 30 h in all contaminated samples using RT-PCR. RT-PCR detection of B. cepacia allowed faster quality control analysis, corrective actions, and process optimization.

Determination of the Acceptable Ambient Light Exposure during Drug Product Manufacturing for Long-Term Stability of Monoclonal Antibodies

Abstract: Monoclonal antibodies (mAbs) are exposed to light during drug product (DP) manufacturing, and the acceptable levels of light exposure needs to be determined based on the impact on product quality. In this study, a mild and more representative light model consisting of ambient light instead of stress light as prescribed by ICH Q1B was used to evaluate the impact of light exposure on mAb DP quality. The immediate effect of ambient light exposure on protein DP quality was determined to be dependent on the amount of light exposure rather than light intensity (up to 5000 lux). The impact on quality of mAbs is product specific due to their differences in light sensitivity, in which mAb II shows larger increases in IEC basic variants and larger decreases in SEC monomer when compared to mAb I after 0.24 million lux hours of light exposure. The acceptable ambient light exposure for mAb II DP manufacturing was determined to be 0.13 million lux hours, in which no impact on product quality was observed after the short-term light exposure. Additionally, real-time storage (5 °C) of the DP after the prescribed ambient light exposure showed no impact to various product quality attributes. The light model used in this study is capable of determining the acceptable amount of ambient light exposure for mAbs, especially during DP manufacturing processes.

Mechanistic Investigation on Grinding-Induced Subvisible Particle Formation during Mixing and Filling of Monoclonal Antibody Formulations

Abstract: Processing equipment involving grinding of two solid surfaces has been demonstrated to induce subvisible particle (SvP) formation in monoclonal antibody (mAb) drug product manufacturing processes. This study elucidated potential stress types associated with grinding action to identify the stress mechanism responsible for SvP formation. Several potential stress types can be associated with the grinding action, including interfacial stresses (air-liquid and liquid-solid), hydraulic/mechanical shear stress, cavitation, nucleation of stressed protein molecules, and localized thermal stress. More than one stress type can synergically impact mAb product quality, making it challenging to determine the primary mode of stress. Our strategy was to assess and rule out some stress types through platform knowledge, rational judgments or via small-scale models, for example, rheometer/rotator-stator homogenizer for hydraulic/mechanical shear stress, sonicator for cavitation, etc. These models may not provide direct evidence but can offer rational correlations. Cavitation, as demonstrated by sonication, proved to be quite detrimental to mAb molecules in forming not just SvPs but also soluble high molecular-weight species (HMWs) as well as low molecular-weight species (LMWs). This outcome was not consistent with that of grinding mAbs between the impeller and the drive unit of a bottom-mounted mixer or between the piston and the housing of a rotary piston pump, both of which formed only SVPs without obvious HMWs and LMWs. In addition, a p-nitrophenol model suggested that cavitation in the bottom-mounted mixer is barely detectable. We attributed the grinding induced, localized thermal effect to be the primary stress to SvP formation based on a high-temperature, spray-drying model. The heat effect of spray drying also caused SvPs, in the absence of significant HMWS and LMWS in spray-dried mAb powders. This investigation provides a mechanistic understanding of the underlying stress mechanism leading to mAb SvP formation as the result of drug product processing involving grinding of solid surfaces.

Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity.

Abstract: A new major chapter dealing with container closure integrity (CCI) was released by the United States Pharmacopeial Convention (USP). Chapter provides a significant amount of education and guidance concerning test methodologies to prove that a system is integral and safe for use. The test method used is only one of the major considerations in approaching the challenge of proving an integral system. This paper takes a holistic review of all the major considerations needed in qualifying a new vial system for container closure integrity. There is substantial interplay among many aspects in the process of sealing a vial. This review helps to define major risks that need to be considered and mitigated and reinforces the need to understand the maximum allowable leakage limit (MALL) that is acceptable for a specific drug application. A typical risk-based approach considers materials, test methods, process, people, environment and equipment. Each of these aspects is considered in some detail along with a recommended process flow for building a best practice, science-based approach. This approach will inform decision making for evaluating the correct combination of components and assuring they are assembled and tested in an appropriate manner. This work, once completed, can be the basis for a vial system platform or specific drug application qualification.

Benchmarking of Sterilizing-Grade Filter Membranes with Liposome Filtration.

Abstract: Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. The sterility of such liposome solutions is typically ensured using 0.2 μm-rated sterilizing-grade membranes, but due to the high viscosity and low surface tension of these formulations, they can cause premature blocking and increased risk of bacterial penetration through a 0.2 μm sterilizing-grade membrane. The low surface tension of liposome solutions affects the contact angle with membrane and reduces bubble point, leading to bacterial penetration through the membrane. This poses a great challenge to select an appropriate sterilizing-grade membrane for a given process and for filter manufacturers to develop a sterilizing-grade membrane that specifically addresses these needs. In this study, the influence of different variables that could affect the total throughput and bacterial retention performance of different membrane types on processing of liposome solutions was evaluated. Based on the results, we conclude that the membrane properties, for example, surface porosity, surface tension, pore size, symmetry/asymmetry, hydrophilicity and liposome properties (e.g., composition, lipid size, and concentration) affect bacterial retention and total throughput capacity. Process parameters such as temperature, pressure, and flow should also be optimized to improve process efficiency.LAY ABSTRACT: Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. Liposome solution cause premature blocking and increased risk of bacterial penetration through a 0.2 μm sterilizing-grade membrane due to their high viscosity and low surface tension. In this study, we demonstrated the total throughput and bacterial retention performance of different sterilizing-grade membranes with liposome solution. Based on the results, we conclude that some sterilizing-grade membranes yield less throughput and bacterial retention compared to other membranes. This is due to liposome formulation and membrane properties. Therefore, it is important to identify the product formulation and membrane properties before selection of a suitable sterilizing-grade filter for a given process application to ensure expected throughput and bacterial retention.

Time-Dependent Testing Evaluation and Modeling for Rubber Stopper Seal Performance.

Abstract: Sufficient rubber stopper sealing performance throughout the entire sealed product life cycle is essential for maintaining container closure integrity (CCI) in the parenteral packaging industry. However, prior publications have lacked systematic considerations for the time-dependent influence on sealing performance that results from the viscoelastic characteristics of the rubber stoppers. In this paper, we report results of an effort to study these effects, by applying both compression stress relaxation (CSR) testing and residual seal force (RSF) testing for time-dependent experimental data collection. These experiments were followed by modeling fit calculations based on the Maxwell-Wiechert theory modified with the Kohlrausch-Williams-Watts (KWW) stretched exponential function, resulting in a nonlinear, time-dependent sealing force model. By employing both testing evaluations and modeling calculations, an in-depth understanding of the time-dependent effects on rubber stopper sealing force was developed. Both testing and modeling data show good consistency, demonstrating that the sealing force decays exponentially over time and eventually levels off because of the viscoelastic nature of the rubber stoppers. The nonlinearity of stress relaxation derives from the viscoelastic characteristics of the rubber stoppers coupled with the large stopper compression deformation into restrained geometry conditions. The modeling fit with capability to handle actual testing data can be employed as a tool to calculate the CSR and RSF throughout the entire sealed product life cycle. In addition to being time-dependent, stress relaxation is also experimentally shown to be temperature-dependent. The present work provides a new, integrated methodology framework and some fresh insights to the parenteral packaging industry for practically and proactively considering, designing, setting up, controlling, and managing stopper sealing performance throughout the entire sealed product life cycle.

Comparative Extractables Study of Autoclavable Polyethersulfone Filter Cartridges for Sterile Filtration

Abstract: Sterile filters are ubiquitous in biopharmaceutical manufacturing processes. Since such filters are in direct contact with the process fluid, profiling of the extractables is of utmost importance. The work presented here reveals the extractables profile from filter cartridges for sterilizing grade filtration, which were obtained from six different vendors. All filters contain a 0.2 μm polyethersulfone (PES) membrane for sterile filtration combined with a PES pre-filter with retention rates spanning from 0.4 to 0.6 μm. These filter cartridges are designed for use in stainless steel housings which allow for in-line steam ster-ilization. A combination of different analytical techniques such as (Headspace) GC-MS, UPLC-HRMS (ESI ionization), ICP-MS, total organic carbon (TOC), non-volatile residue (NVR), conductivity and pH value were applied to develop a comprehensive extractables profile on a qualitative and semi-quantitative basis. Pure ethanol and purified water were used as extraction media. The extractables pro-file consisted of various polyolefin related extractables, additives such as antioxidants (AO) and degra-dation products thereof, hydrocarbons and processing aids in addition to membrane related extractables.

Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development

Abstract: Monoclonality of mammalian cell lines used for production of biologics is a regulatory expectation and one of the attributes assessed as part of a larger process to ensure consistent quality of the biologic. Historically, monoclonality has been demonstrated through statistics generated from limiting dilution cloning or through verified flow cytometry methods. A variety of new technologies are now on the market with the potential to offer more efficient and robust approaches to generating and documenting a clonal cell line. Here we present an industry perspective on approaches for the application of imaging and integration of that information into a regulatory submission to support a monoclonality claim. These approaches represent the views of a consortium of companies within the BioPhorum Development Group and include case studies utilising imaging technology that apply scientifically sound approaches and efforts in demonstrating monoclonality. By highlighting both the utility of these alternative approaches and the advantages they bring over the traditional methods, as well as their adoption by industry leaders, we hope to encourage acceptance of their use within the biologics cell line development space and provide guidance for regulatory submission using these alternative approaches. LAY ABSTRACT: In the manufacture of biologics produced in mammalian cells, one recommendation by regulatory agencies to help ensure product consistency, safety, and efficacy is to produce the material from a monoclonal cell line derived from a single, progenitor cell. The process by which monoclonality is assured can be supplemented with single-well plate images of the progenitor cell. Here we highlight the utility of that imaging technology, describe approaches to verify the validity of those images, and discuss how to analyze that information to support a biologic filing application. This approach serves as an industry perspective to increased regulatory interest within the scope of monoclonality for mammalian cell culture–derived biologics.

Methods to Determine the Silicone Oil Layer Thickness in Sprayed-On Siliconized Syringes

Abstract: The silicone lubricant layer in prefilled syringes has been investigated with regards to siliconization process performance, prefilled syringe functionality, and drug product attributes, such as subvisible particle levels, in several studies in the past. However, adequate methods to characterize the silicone oil layer thickness and distribution are limited, and systematic evaluation is missing. In this study, white light interferometry was evaluated to close this gap in method understanding. White light interferometry demonstrated a good accuracy of 93–99% for MgF2 coated, curved standards covering a thickness range of 115–473 nm. Thickness measurements for sprayed-on siliconized prefilled syringes with different representative silicone oil distribution patterns (homogeneous, pronounced siliconization at flange or needle side, respectively) showed high instrument (0.5%) and analyst precision (4.1%). Different white light interferometry instrument parameters (autofocus, protective shield, syringe barrel dimensions input, type of non-siliconized syringe used as base reference) had no significant impact on the measured average layer thickness. The obtained values from white light interferometry applying a fully developed method (12 radial lines, 50 mm measurement distance, 50 measurements points) were in agreement with orthogonal results from combined white and laser interferometry and 3D-laser scanning microscopy. The investigated syringe batches (lot A and B) exhibited comparable longitudinal silicone oil layer thicknesses ranging from 170–190 nm to 90–100 nm from flange to tip and homogeneously distributed silicone layers over the syringe barrel circumference (110– 135 nm). Empty break-loose (4–4.5 N) and gliding forces (2–2.5 N) were comparably low for both analyzed syringe lots. A silicone oil layer thickness of 100–200 nm was thus sufficient for adequate functionality in this particular study. Filling the syringe with a surrogate solution including short-term exposure and emptying did not significantly influence the silicone oil layer at the investigated silicone level. It thus appears reasonable to use this approach to characterize silicone oil layers in filled syringes over time. The developed method characterizes non-destructively the layer thickness and distribution of silicone oil in empty syringes and provides fast access to reliable results. The gained information can be further used to support optimization of siliconization processes and increase the understanding of syringe functionality. LAY ABSTRACT: Silicone oil layers as lubricant are required to ensure functionality of prefilled syringes. Methods evaluating these layers are limited, and systematic evaluation is missing. The aim of this study was to develop and assess white light interferometry as an analytical method to characterize sprayed-on silicone oil layers in 1 mL prefilled syringes. White light interferometry showed a good accuracy (93–99%) as well as instrument and analyst precision (0.5% and 4.1%, respectively). Different applied instrument parameters had no significant impact on the measured layer thickness. The obtained values from white light interferometry applying a fully developed method concurred with orthogonal results from 3D-laser scanning microscopy and combined white light and laser interferometry. The average layer thicknesses in two investigated syringe lots gradually decreased from 170–190 nm at the flange to 100–90 nm at the needle side. The silicone layers were homogeneously distributed over the syringe barrel circumference (110–135 nm) for both lots. Empty break-loose (4–4.5 N) and gliding forces (2–2.5 N) were comparably low for both analyzed syringe lots. Syringe filling with a surrogate solution, including short-term exposure and emptying, did not significantly affect the silicone oil layer. The developed, non-destructive method provided reliable results to characterize the silicone oil layer thickness and distribution in empty siliconized syringes. This information can be further used to support optimization of siliconization processes and increase understanding of syringe functionality.

The Impact of Quality Culture on Operational Performance - An Empirical Study from the Pharmaceutical Industry

Abstract: Quality culture as an enabler of high-quality performance and subsequently as a source of competitive advantage is increasingly discussed among operational excellence (OPEX) and quality executives Research studies indicate an impact of quality culture on performance, especially on the success of quality improvement programs, such as Total Quality Management initiatives A continual challenge in quality culture research, however, remains the lack of practical and accepted metrics to assess culture In 2014, the Parental Drug Association (PDA) conducted a quality culture survey within the pharmaceutical industry The results indicate a positive and significant correlation between quality (culture) behavior of a production site9s employees and quality (system) maturity, which represents the maturity of the quality system in place As the maturity of the quality system is more comfortable to assess by objective criteria, the positive correlation between quality (culture) behavior and quality (system) maturity may be exploited by using the latter as an indicator for quality culture This paper confirms this positive relationship by exploring the comprehensive St Gallen OPEX database for pharmaceutical production plants Furthermore, data analysis shows that high-performing production sites, regarding timely provision of high-quality drugs, reveal a higher level of both quality (system) maturity and quality (culture) behavior than low-performing sites

Quality of Medicines in Portugal: A Retrospective Review of Medicine Recalls (2000-2015).

Abstract: INFARMED, the Portuguese national health authority, alerts the general public and healthcare professionals about quality or safety issues detected in health products. The present study analyses substandard medicines recalls in Portugal between 2005 and 2015. All 338 alerts for medicine recalls were analysed, which represents a total of 378 drugs withdrawn. Despite the fact that the total number of medicine alerts has increased during the past decade, the number of actual medicine recalls remained relatively constant. The number of batches affected in each recall varies from only one to several batches. In addition, 294 of the alerts are related to voluntary recalls, i.e., initiated by the marketing authorisation holder, whereas only 40 were mandatory recalls. There are marketing authorisation holders that have had several medicine recalls over the period studied. The main cause of product recall was the pharmaceutical dosage form, followed by packaging problems. 42% of the wtihdrawn medicines are from solid oral forms, a value slightly higher than that obtained for the injectables group. Finally, substandard medicines have been accessible in the Portuguese market for a period that varied between 1 month and over 4 years. The data seem to show that the number of substandard medicines in Portugal has not been increasing. However, this may be due to a variety of causes, i.e., better performance of the industry, non-detection of these cases, etc.

Delamination Propensity of Glass Containers for Pharmaceutical Use: A Round Robin Activity Looking for a Predictive Test.

Abstract: Delamination, which is the formation of flakes in drug products due to specific and localized corrosion of glass vials, is a rare but very serious problems, and the FDA (U.S. Food and Drug Administration) put a warning to the pharma industry in 2011. Technical Committee TC12 of the International Commission on Glass (ICG) was created in 2012, with the aim to study the problems related to pharma packaging. The first task of TC12 was to address the problem of predicting the propensity of glass vials to delamination, leaving the study of the mechanism(s) of flake formation as a possible future activity. This paper reports on the results obtained in a round robin test which involved all the labs of the companies represented in the Technical Committee. Five types of vials with different expected delamination propensity were tested using a protocol which includes autoclaving at 121 °C of vials filled with a NaCl solution adjusted to pH 8 with NaOH solution, a coloration test, and ICP-OES determination of Si, B and Al. Although no flake formation was observed, the results shown that the combination of strong coloration at the bottom of vials and high silicon concentration in the solution is correlated to an observable morphological modification/corrosion of the inner surface of vials in the bottom region. The test protocol is therefore useful for checking the quality of vials with respect to the propensity to corrosion. With respect to delamination, no direct correlation with the testing results could be obtained yet.. The method allows catching differences in the corrosion behavior mainly between sets of vials with comparable surface/volume ratio.

Microbiological Test Data—Assuring Data Integrity

Abstract: Marketed drugs and devices possess specifications including critical microbiological quality attributes purposed to assure efficacy and patient safety. These attributes are legislated requirements intended to protect the recipient patient. Sampling, microbiological testing, interpretation of data for final products, raw materials and intermediates all contribute to a cohesive assessment in the assurance of finished product quality. Traditional culture-based microbiological methods possess inherent and unavoidable variability, recognized by the compendia and which might lead to erroneous conclusion pertaining to product quality. Such variability has been associated and intrinsically linked with data integrity issues; manufacturers have subsequently been encouraged by regulatory authorities to introduce multiple microbiologists or checks to prevent such issues. Understanding microbiological variability is essential such that genuine data integrity issues are identified. Furthermore, a range of meaningful preventative strategies are feasible beyond increasing the capacity of the quality control microbiological laboratory. This short review describes the legislative requirements, inherent microbiological variability and realistic actions and activities that genuinely assure patient safety.

Achieving “Zero” Defects for Visible Particles in Injectables

Abstract: The reduction of visible particles in injectable products is an important element in the consistent delivery of high-quality parenteral products. An important part of this effort is the control of particles that may emanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF) has undertaken the task of developing test methods to assess the cleanliness of primary packaging components used in the manufacture of sterile injectable products. Further work is focused on end-to-end analysis of the supply chain to identify additional points where particles may enter the finished product workflow. This includes shipment, receipt, transfer and fill and finishing operations. This information and appropriate corrective actions and control methods, coupled with appropriate patient risk-based acceptance limits, are intended to provide better and more consistent supply of injectable products that meet current compendial and Good Manufacturing (GMP) expectations. Aligning control limits between supplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formation of a task force to address these needs and current progress to date.

Proceedings of the 2017 Viral Clearance Symposium, Session 4: Submission Strategies.

Abstract: Appropriate performance of virus validation studies and testing of unprocessed bulk harvests for retrovirus particle count are procedures in the demonstration of an acceptable level of viral safety for cell-derived biotechnology products. Product-specific validation studies on virus reduction with two model viruses [usually murine leukemia virus (MuLV) and a parvovirus] performed in duplicate runs are standard for clinical trial applications. For the retroviral safety margin, a 6 log reduction is normally expected. Retroviral particle counts are measured traditionally by transmission electron microscopy (TEM) and are commonly performed at contract laboratories. These procedures are quite time-consuming and can be associated with significant costs. In particular, the time factor is a hurdle for companies that want to quickly bring their new products to the clinic. In this session, several strategies on how to lower time, cost, and workload in the evaluation of viral safety for early clinical trial applications, while still ensuring sufficient level of viral safety of the product, were presented. In addition, virus reduction strategies for molecules that do not have the standard antibody structure are presented. Also presented in this session is the feasibility of the use of retrovirus-like particle (RVLP) in the prevalidation of virus removal and the use of quantitative polymerase chain reaction (qPCR) as an alternative to infectivity assays in virus validation studies as well as its use as an alternative to quantitative TEM analysis for determining RVLP count in the bulk harvest of a perfusion bioreactor.LAY ABSTRACT: In this session, several strategies on how to lower time, cost, and workload in the evaluation of viral safety for early clinical trial applications of cell-derived biotechnology products, while still ensuring sufficient level of viral safety of the product, were presented. In addition, virus reduction strategies for molecules that do not have the standard antibody structure are presented. Also presented in this session is the feasibility of the use of retrovirus-like particle (RVLP) in the prevalidation of virus removal and the use of quantitative polymerase chain reaction (qPCR) as an alternative to infectivity assays in virus validation studies as well as its use as an alternative to quantitative TEM analysis for determining RVLP count in the bulk harvest of a perfusion bioreactor.

Introducing the Alba® Primary Packaging Platform. Part 1: Particle Release Evaluation

Abstract: The sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failures as worst case scenario. This potential incompatibility - and the consequent formulation instability due to the interactions between the drug and the primary container surface - may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, silicone oil droplets or other particles. The Alba primary packaging platform was designed in order to have the same interface between the drug and the glass container surface on the different primary packaging containers to minimize the emergence of instabilities at later stages during the formulation development. The Alba containers are internally treated with an innovative cross-linked coating based on silicone oil lubricant and the additional rubber components have been selected to minimize the possible differences between the container typologies. This paper shows in deep details the subvisible particle release reduction and the comparability of the performances of different containers, obtained using such technology. To demonstrate this improvement, different analytical methods for particle measurement were used on bulk containers, Alba treated ones and containers from a standard production (spray-on siliconization). Considering that Alba containers are conform to the standard compendial testing and the amount of particles released from Alba coated syringes resulted comparable to the bulk ones for the first two mildly stressful methods, it was decided to develop and apply a more challenging method, such as an autoclave treatment for 1 hour at 121°C, to better highlight the performances of this innovative technology. The data obtained, under the most stressful conditions, shows a substantial reduction in the released particle concentrations compared to a spray-on siliconized container, and comparable performances for all the containers included in the Alba platform. The latter could heavily reduce the drug formulation development timings, facilitating the transition from a container to another.

Life Cycle Assessment of Reusable and Disposable Cleanroom Coveralls.

Abstract: Cleanroom garments serve a critical role in such industries as pharmaceuticals, life sciences, and semiconductor manufacturing. These textiles are available in reusable and disposable alternatives. In this report, the environmental sustainability of cleanroom coveralls is examined using life cycle assessment technology. The complete supply chain, manufacture, use, and end-of-life phases for reusable and disposable cleanroom coveralls are compared on a cradle-to-end-of-life cycle basis. Three industry representative coveralls are examined: a reusable woven polyethylene terephthalate (PET) coverall, a disposable flash spunbonded high-density polyethylene (HDPE) coverall, and a disposable spunbond-meltblown-spunbond polypropylene (SMS PP) coverall. The reusable cleanroom coverall system shows substantial improvements over both disposable cleanroom coverall systems in all environmental impact categories. The improvements over the disposable HDPE coverall were 34% lower process energy (PE), 23% lower natural resource energy (NRE), 27% lower greenhouse gas (GHG) emissions, and 73% lower blue water consumption. The improvements over the disposable SMS PP coverall were 59% lower PE, 56% lower NRE, 57% lower GHG emissions, and 77% lower blue water consumption. In addition, the reusable system shows a 94–96% reduction in solid waste to the landfill from the cleanroom facility. Between the two disposable cleanroom coveralls, the flash spunbonded HDPE coverall shows a measurable environmental improvement over the SMS PP coverall. LAY ABSTRACT: Pharmaceutical drugs are manufactured and handled in controlled environments called cleanrooms to ensure the safety and quality of products. In order to maintain strict levels of cleanliness, cleanroom personnel are required to wear garments such as coveralls, hoods, and gloves that restrict the transfer of particles from the person to the environment. These garments are available in reusable and disposable types. Cleanroom operators consider a number of factors when selecting between reusable and disposable garments, including price, comfort, and environmental sustainability. In this report, the environmental sustainability of reusable and disposable cleanroom coveralls is examined using a technique called life cycle assessment. With this technique, environmental parameters such as energy use and greenhouse gas emissions are quantified and compared for three market representative cleanroom coveralls, from raw material extraction through manufacturing, use, and final disposal. Reusable coveralls were found to substantially outperform disposable coveralls in all environmental parameters examined. This is an important conclusion that supports cleanroom companies that select reusable coveralls to be more sustainable.

A QRM Discussion of Microbial Contamination of Non-sterile Drug Products, Using FDA and EMA Warning Letters Recorded between 2008 and 2016

Abstract: Microbial quality control of non-sterile drug products is a concern to regulatory agencies and the pharmaceutical industry since the 19609s. Despite being an old challenge to companies, microbial contamination still affects a high number of manufacturers of non-sterile products. Consequences go well beyond the obvious direct costs related to batch rejections or product recalls, as human lives and a company9s reputation are significantly impacted as well if such event occurs. To better manage this type of events and establish effective mitigation strategies, it is necessary to understand the microbial hazards involved in the manufacturing processes of non-sterile drug products, be able to evaluate their potential impact on final product quality and apply mitigation actions . Herein we discuss the most likely root causes involved in microbial contaminations referenced in Warning letters (WLs) issued by the US Health Authorities and Non-compliance reports issued by European Health Authorities, over a period of several years. The QRM tools proposed were applied to the data gathered from those databases and a generic risk ranking is provided based on a panel of non-sterile drug product manufacturers that was assembled and given the opportunity to perform the risk assessments. That panel identified gaps and defined potential mitigation actions, based on their own experience of potential risks expected for their processes. Major findings clearly indicate that the manufacturers affected by the WLs considered, should focus their attention on the improvement of processes and controls, specially raw materials and primary packaging quality control (QC). A stronger enforcement by health authorities, of better in-process contamination controls, would be beneficial.

Inhibiting sterilization-induced oxidation of large molecule therapeutics packaged in plastic parenteral vials

Abstract: For many years, glass has been the default material for parenteral packaging, but the development of advanced plastics such as cyclic olefin polymers and the rapidly increasing importance of biologic drugs have provided new choices, as well as more stringent performance requirements. In particular, many biologics must be stored at non-neutral pH, where glass is susceptible to hydrolysis, metal extraction, and delamination. Plastic containers are not susceptible to these problems, but suffer from higher gas permeability and a propensity for sterilization-induced radical generation, heightening the risk of oxidative damage to sensitive drugs. This study evaluates the properties of a hybrid material, SiOPlas™, in which an ultrathin multilayer coating is applied to the interior of cyclic olefin polymer containers via plasma-enhanced chemical vapor deposition. Our results show that the coating decreases oxygen permeation through the vial walls 33-fold compared to uncoated cyclic olefin polymers, which should allow for improved control of oxygen levels in sensitive formulations. We also measured degradation of two biologic drugs that are known to be sensitive to oxidation, teriparatide and erythropoietin, in gamma and electron beam sterilized SiOPlas™, glass, and uncoated cyclic olefin polymer vials. In both cases, solutions stored in SiOPlas™ vials did not show elevated susceptibility to oxidation compared to either glass or unsterilized controls. Taken together, these results suggest that hybrid materials such as SiOPlas™ are attractive choices for storing high-value biologic drugs.LAY ABSTRACT: One of the most important functions of parenteral drug containers is safeguarding their contents from damage, either chemical or physical. Glass has been the container material of choice for many years, but concerns over breakage and vulnerability to chemical attack at non-neutral pH have spurred the rise of advanced plastics as alternatives. Plastics solve many problems associated with glass but introduce several of their own, including increased gas permeation and generation of oxidizing radicals during sterilization. In this article, we evaluate SiOPlas™, a hybrid material consisting of plastic with a thin multilayer coating applied to the interior, for its ability to overcome these two problems. We find that SiOPlas™ is much less permeable to oxygen than uncoated plastic, and that two biologic drugs stored in gamma and electron beam sterilized SiOPlas™ vials do not display elevated levels of oxidation compared to either glass or unsterilized vials. This suggests that hybrid materials such as SiOPlas™ can exhibit the best qualities of both glass and plastic, making them attractive materials for storing high-value parenteral drugs.

Retention of Acholeplasma laidlawii by Sterile Filtration Membranes: Effect of Cultivation Medium and Filtration Temperature

Abstract: This experimental study compares cell size, zeta potential, and the ability to penetrate tailor-made size exclusion membrane filters of mycoplasma Acholeplasma laidlawii cultivated in five different cultivation media. The influence of relevant filtration process parameters, in particular transmembrane pressure and filtration temperature, on their respective retention was tested. The impact of the filtration temperature was further evaluated for the Gram-negative bacteria species Brevundimonas diminuta, the Gram-positive bacteria species Staphylococcus epidermidis, the Pseudomonas phage PP7, and the mycoplasma species Mycoplasma orale. The findings were correlated to the different mechanical properties of the particles, especially also with respect to the different bacterial cell envelopes found in those species. This study suggests that mycoplasma, surrounded by a flexible lipid bilayer, are significantly susceptible to changes in temperature, altering the stiffness of the cell envelope. Mycoplasma retention could thus be increased significantly by a decreased filtration temperature. In contrast, Gram-negative and Gram-positive bacteria species, with a cell wall containing a cross-linked peptidoglycan layer, as well as bacteriophages PP7 exhibiting a rigid protein capsid, did not show a temperature-dependent retention within the applied filtration temperatures between 2 and 35 °C. The trends of the retention of A. laidlawii with increasing temperature and transmembrane pressure were independent of cultivation media. Data obtained with mycoplasma M. orale suggest that the trend of mycoplasma retention at different filtration temperatures is also independent of the membrane pore size and thus retention level. LAY ABSTRACT: Media in biopharmaceutical processes are sterile-filtered to prevent them from bacterial contamination. Mycoplasma represent a relevant class of bacteria. In this publication it is shown that mycoplasma cell size depends on the media they are cultivated in. Membranes used for sterile filtration retain bacteria predominantly by size exclusion. Thus, an altered cell size can result in different retention values. Another characteristic of mycoplasma is the flexible lipid bilayer and the absence of a rigid cell wall. The lipid bilayer can undergo a phase transition from a gel to a liquid-crystal phase at a certain temperature, which makes it stiffer at lower temperatures. A higher stiffness can result in higher retention values during filtration, as the deformability of the mycoplasma cell is lower and the cell does not squeeze through the membrane pores. Abbreviations: ALCM: A. laidlawii culture medium; ASTM: American Society for Testing and Materials; ATCC: American Type Culture Collection; CFU/mL: colony-forming units per milliliter; DLS: Dynamic light scattering; LRV: Log reduction value; PES: Polyethersulfone; PFU/mL: Plaque-forming units per milliliter; PSD: Particle size distribution; PVP: Polyvinylpyrrolidone; SDS: Sodium dodecyl sulfate; SEM: Scanning electron microscopy; SLB: Saline lactose broth; TMP: Transmembrane pressure; TSB: Tryptic soy broth

Sealing Behaviour of Container Closure Systems under Frozen Storage Conditions: Nonlinear Finite Element Simulation of Serum Rubber Stoppers.

Abstract: There has been a growing interest in recent years in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products. Considering that the glass transition temperature (Tg) of butyl rubber stoppers used in container closure systems (CCSs) is between −55 °C to −65 °C, a storage or shipment temperature of a frozen product below the Tg of the rubber stopper may require special attention because below the Tg the rubber becomes more plastic like and loses its elastic (sealing) characteristics. Thus, they risk not maintaining container closure integrity (CCI). Given that the rubber regains its elastic properties and reseals after rewarming to ambient temperature, leaks during frozen temperature storage and transportation are transient and the CCI methods used at room temperature conditions are unable to confirm CCI in the frozen state. Hence, several experimental methods have been developed in recent years in order to evaluate CCI at low temperatures. Finite element (FE) simulations were applied in order to investigate the sealing behaviour of rubber stoppers for the drug product CCS under frozen storage conditions. FE analysis can help in reducing the experimental design space and thus the number of measurements needed, as they can be used as an add-on to experimental testing. Several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case CCS geometric tolerances, and capping pressure. The results of these calculations have been validated with experimental data derived from laboratory experiments (CCI at low temperatures), and a concept for tightness has been developed. It has been concluded that FE simulations have the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on CCI) when dealing with frozen drug products. LAY ABSTRACT: The growing interest in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products has led to the development of a number of experimental methods to evaluate container closure integrity at low temperatures. The application of finite element simulations could aid in the investigation of the sealing behaviour of rubber stoppers for drug product container closure systems under frozen storage conditions by simplifying the experimental design space and the number of experimental measurements needed. In this work several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case container closure system geometric tolerances, and capping pressure. The results have been further validated with experimental data derived from laboratory experiments and a concept for tightness was developed. In conclusion, finite element simulations have shown the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on container closure integrity) when dealing with frozen drug products.

A Model of Risk Analysis in Analytical Methodology for Biopharmaceutical Quality Control

Abstract: One key quality control parameter for biopharmaceutical products is the analysis of residual cellular DNA. To determine small amounts of DNA (around 100 pg) that may be in a biologically derived drug substance, an analytical method should be sensitive, robust, reliable, and accurate. In principle, three techniques have the ability to measure residual cellular DNA: radioactive dot-blot, a type of hybridization; threshold analysis; and quantitative polymerase chain reaction. Quality risk management is a systematic process for evaluating, controlling, and reporting of risks that may affects method capabilities and supports a scientific and practical approach to decision making. This paper evaluates, by quality risk management, an alternative approach to assessing the performance risks associated with quality control methods used with biopharmaceuticals, using the tool hazard analysis and critical control points. This tool provides the possibility to find the steps in an analytical procedure with higher impact on method performance. By applying these principles to DNA analysis methods, we conclude that the radioactive dot-blot assay has the largest number of critical control points, followed by quantitative polymerase chain reaction, and threshold analysis. From the analysis of hazards (i.e., points of method failure) and the associated method procedure critical control points, we conclude that the analytical methodology with the lowest risk for performance failure for residual cellular DNA testing is quantitative polymerase chain reaction.LAY ABSTRACT: In order to mitigate the risk of adverse events by residual cellular DNA that is not completely cleared from downstream production processes, regulatory agencies have required the industry to guarantee a very low level of DNA in biologically derived pharmaceutical products. The technique historically used was radioactive blot hybridization. However, the technique is a challenging method to implement in a quality control laboratory: It is laborious, time consuming, semi-quantitative, and requires a radioisotope. Along with dot-blot hybridization, two alternatives techniques were evaluated: threshold analysis and quantitative polymerase chain reaction. Quality risk management tools were applied to compare the techniques, taking into account the uncertainties, the possibility of circumstances or future events, and their effects upon method performance. By illustrating the application of these tools with DNA methods, we provide an example of how they can be used to support a scientific and practical approach to decision making and can assess and manage method performance risk using such tools. This paper discusses, considering the principles of quality risk management, an additional approach to the development and selection of analytical quality control methods using the risk analysis tool hazard analysis and critical control points. This tool provides the possibility to find the method procedural steps with higher impact on method reliability (called critical control points). Our model concluded that the radioactive dot-blot assay has the larger number of critical control points, followed by quantitative polymerase chain reaction and threshold analysis. Quantitative polymerase chain reaction is shown to be the better alternative analytical methodology in residual cellular DNA analysis.

Multiproduct Resin Reuse for Clinical and Commercial Manufacturing—Methodology and Acceptance Criteria

Abstract: Chromatography resins used for purifying biopharmaceuticals are generally dedicated to a single product In good manufacturing practice (GMP) facilities that manufacture a limited amount of any particular product, this practice can result in the resin being used for a fraction of its useful life A methodology for extending resin reuse to multiple products is described With this methodology, resin and column performance, product carryover, and cleaning effectiveness are continually monitored to ensure that product quality is not affected by multiproduct resin reuse (MRR) Resin and column performance is evaluated in terms of (a) system suitability parameters, such as peak-shape and transition, and height equivalent theoretical plate (HETP) data; (b) key operating parameters, such as flow rate, inlet pressure, and pressure drop across the column; and (c) process performance parameters, such as impurity profiles, product quality, and yield Historical data are used to establish process capability limits (PCLs) for these parameters Operation within the PCLs provides assurance that column integrity and binding capacity of the resin are not affected by MRR Product carryover defined as the carryover of the previously processed product (A) into a dose of the subsequently processed product (B) (COA→B), should be acceptable from a predictive patient safety standpoint A methodology for determining COA→B from first principles and setting acceptance limits for cleaning validation is described Cleaning effectiveness is evaluated by performing a blank elution run after inter-campaign cleaning and prior to product changeover The acceptance limits for product carryover (COA→B) are more stringent for MRR than for single-product resin reuse Thus, the inter-campaign cleaning process should be robust enough to consistently meet the more stringent acceptance limits for MRR Additionally, the analytical methods should be sensitive enough to adequately quantify the concentration of the previously processed product (A) and its degradants in the eluent General considerations for designing small-scale chromatographic studies for process development are also described These studies typically include process-cycling runs with multiple products followed by viral clearance studies with a panel of model viruses Small-scale studies can be used to optimize cleaning parameters, predict resin performance and product quality, and estimate the number of multiproduct purification cycles that can be run without affecting product quality The proposed methodology is intended to be broadly applicable; however, it is acknowledged that alternative approaches may be more appropriate for specific scenarios LAY ABSTRACT: Chromatography resins used for purifying biopharmaceuticals are generally dedicated to a single product In good manufacturing practice (GMP) facilities that make a limited amount of any particular product, this practice can result in the resin being used for a fraction of its useful life A methodology for extending resin reuse to multiple products is described With this methodology, resin and column performance, product carryover, and cleaning effectiveness are continually monitored to ensure that product quality is not affected by multiproduct resin reuse General considerations for designing small-scale chromatographic studies for process development are described These studies typically include process-cycling runs with multiple products followed by viral clearance studies with a panel of model viruses Small-scale studies can be used to optimize cleaning parameters, predict resin performance and product quality, and estimate the number of multiproduct purification cycles that can be run without impacting product quality The proposed methodology is intended to be broadly applicable; however, it is acknowledged that alternative approaches may be more appropriate for specific scenarios

Demonstrating Pharmaceutical Quality System Effectiveness and Driving Continual Improvement: Evidence-Based Risk Reduction

Abstract: Product knowledge grows and evolves during the life of a product. In order to maintain a state of control and deliver product with consistent quality throughout its commercial life, continuous improvement and product lifecycle management become essential. The practical link between product and process knowledge, risk-based control strategies, and continual improvement and innovation can be made stronger through evidence-based risk reduction. This paper introduces the concept of evidence-based risk reduction within the continual improvement framework. It presents how regulatory relief and flexibility in post-approval change management and overall product lifecycle management can likely only be achieved via (1) effective application of science and risk-based concepts and (2) demonstrated effectiveness of the pharmaceutical quality system in assuring a state of control.

Method Verification Requirements for an Advanced Imaging System for Microbial Plate Count Enumeration

Abstract: The Growth Direct™ System that automates the incubation and reading of membrane filtration microbial counts on soybean-casein digest, Sabouraud dextrose, and R2A agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation. Based on the recommendations in USP Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation. LAY ABSTRACT: The Growth Direct™ System that automates the incubation and reading of microbial counts on membranes on solid agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation time. Based on the recommendations in USP Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation.

Evaluation of an ATP-Bioluminescence Rapid Microbial Screening Method for In-Process Biologics

Abstract: This study compared an ATP-based bioluminescence rapid microbial method (RMM) with a conventional sterility method for biologic sample testing. The RMM is based on a comparison of ATP levels in inoculated and uninoculated microbiological growth medium samples following growth enrichment incubation. The biologics samples qualified in this study were recombinant monoclonal antibodies and hybridoma cell culture supernatants. Initially, the lot-to-lot variation in background ATP of these samples posed significant challenges. Two strategies to increase the signal-to-noise ratio (positive result/background ATP) were evaluated: enzyme-based signal amplification and reduction of the broth-based noise through broth selection. Following qualification of the RMM for antibody and cell culture samples, the RMM was also utilized for rapid screening of several sources of purified water. This ATP-based RMM has proved invaluable in routine testing of diverse biologic samples at our discovery research site and plays a key role in investigation of contaminated samples.