Introduction
Biopharmaceuticals are complicated products to make because of their unique sensitive structures that are normally difficult to define in molecular terms. It is difficult to achieve consistency in their composition often resulting in challenges to assure product quality, and therefore to ensure safety and efficacy [1, 2]. The “Roll out” of a harmonized pharmaceutical quality system, the Quality-by-Design (QbD) based on the Process Analytical Technology (PAT), ICH Q8/Q9/Q10 guidelines has opened up an opportunity for those pharmaceutical industries that have the quest for continuous quality improvement to produce safer, more efficacious therapeutics and to produce them more cost-effectively [3-7]. The gist of the expectations from QbD is that the product and process performance characteristics should be scientifically designed to meet specific objectives, not empirically derived from performance of test batches, and good product quality should represent an acceptably low risk of failing to achieve the desired clinical attributes. This requires several key elements such as target product profile, prior scientific knowledge, product/process development, product/process design space, and control strategy to be defined and incorporated into the studies, and included in the dossier. The interpretations and scope of these elements are well defined/established in the small molecule pharmaceuticals, however, it is at its nascent stages in the biopharmaceuticals due to the unique challenges associated with the development and manufacturing of API and drug product. Its discussion will be helpful to decipher the concepts and discuss with illustrative examples especially when there is dearth of information. It becomes more challenging when it is applied to the freeze dried product due to the complex lyophilization process and its performance dependency on formulation composition besides several other factors.
In this article, we attempt to briefly explain the definitions and scope of the key elements of QbD and their applications to the drug product formulation and freeze drying process.
Drug Product Formulation
The first step towards the implementation of QbD is to define the Quality Target Product Profile (QTPP) which is a template where the drug sponsor identifies and lists drug labeling concepts and documents the intended studies to support those concepts [8]. This becomes the ultimate goals and a planning tool of the drug discovery and development program. The QTPP comprise of several key sections and include the following at a particular time in development: Description- (Information relating to the completed/ planned studies to support the target with Protocol IDs and submission dates. It should include detail regarding the treatment, prevention of specific disease), Indications and Usage, Dosage and Administration, Dosage Forms and Strengths, Contraindications, Warning and Precautions, Adverse Reactions, Drug Interactions, Clinical Pharmacology, Use in specific populations, Drug Abuse and Dependence, Overdosage, Nonclinical Toxicology, Clinical Studies, References, How supplied/Storage and handling, Patient Counseling Information with each section containing (1) Target (2) Annotations and (3) Comments. It provides the information necessary for an open and constructive communication that will not only ensure that the drug sponsor and the FDA have the same understanding of the risks involved with the proposed labeling but also potentially minimize the risk of late-stage development failures, ensure the safety and efficacy data availability in a timely manner, and improve labeling content, and potentially reduce the total time involved with drug development.
The product development involves the development of formulation and manufacturing processes, and at least in the case of lyophilized drug product development, they should be developed hand in hand as they are very interrelated, what is in the formulation dictates the process and vice versa. The objective of the formulation development is to identify the right composition and configuration for API that maintains and supports the target product profile as it goes through various unit operations of manufacturing and during shelf-life. This becomes possible when interactions between formulation and process parameters are fully understood and well controlled and, application of QbD elements just helps to achieve that.
The first step towards the development of a robust formulation based upon QbD principles would be agreed on the desired outcomes in terms of the QTPP. For a lyophilized drug product, it may include type of dosage form, protein content per vial or deliverable volume with protein concentration, mode of administration (sub-cutaneous or IV), reconstitution media and reconstitution volume, mode of reconstitution, reconstitution time, under vacuum or not, final presentation (device or reconstitution device etc.), type of container (for drug product and reconstitution medium), shelf-life, postreconstitution stability and biocompatibility. Once the formulation related QTPPs are defined, the QbD principles recommend use of Prior-Knowledge and past experience with similar molecule pertaining to modes of instability, excipient characteristics and their behavior upon freeze drying to identify the initial composition of the formulation and make initial risk assessment For example, if the molecule belongs to class of monoclonal antibodies, we know from our experience that the formulation would comprise of sucrose and polysorbate to protect against the interfacial, colloidal and conformational instabilities and, acetate or other buffers to maintain and provide buffer capacity in the pH range besides inclusion of a bulking agent (mannitol or glycine), depending upon protein concentration to provide crystalline matrix to the cake [9]. This initial formulation can be further studied with limited experiments to define the target formulation. This exercise of using Prior-Knowledge and leverage on the lesson learned from mistakes and successes, based on historical data, in the early design of the formulation will not only help to build quality into the design but also prevents industries from enduring excessive costs arising from redoing work already ‘done’.
Once the target formulation is identified and developed, the next step is to test the robustness of the target formulation against the quality attributes by varying the formulation components and exposing to various solution and process conditions. This robustness need to be tested both at a pilot and commercial scale as some stresses are scaledependent. Prior-knowledge and experience is used to create a list of formulation critical quality attributes (CQAs) that relates to or affects the formulation specific QTPPs and a typical lists of CQAs for a protein formulation for freeze drying would comprise of freeze drying properties (collapse temperature, Tg’ etc.) cake appearance, reconstitution time and residual moisture besides protein purity (chemical changes, aggregates, clips, visible and subvisible particles). These attributes are subject to further refinement during development, based upon the characterization of the product, or new findings. A similar list of parameters comprising of formulation components (excipients, buffer components, surfactant, raw materials impurities and protein concentrations), solution conditions (pH, temperature, ionic strength etc.), process conditions (Freeze/thaw, transportation, photo exposure, mixing, hold-time, UF/DF, filtration, filling, lyophilization, inspection) and components (IV bags, tubings, vials, syringes, stoppers, devices) is created and affects of these parameters on CQAs are studied. There are several ways of studying this that includes an initial scoring exercise based on Prior-Knowledge followed by factorial design and the purpose is to understand the interactions and identify the parameters that significantly impacts the CQAs, termed as critical process parameters (CPP). These CPPs are further characterized using design of experiments (DOE) to draw the upper and lower limits, and construct the “Design Space” within which quality is assured. As defined in ICHQ8(R1) guideline, the Design space is ‘the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval’ (ICH Q8(R1). The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided. It is the knowledge gained and submitted to the authorities, and not the volume of data collected, that forms the basis for science- and risk-based submissions and regulatory evaluations. Nevertheless, appropriate data demonstrating that this knowledge is based on sound scientific principles should be presented with each application (ICH Q8(R1).
At the end of the construction of “Design Space”, based upon the understanding of the criticality of the components of the formulation, the formulation and process development team need to discuss and agree on where in the formulation steps to install which controls to consistently ensure quality. There will be some ingredients of the formulation that will have largest influence on the process performance and drug product quality attributes that will require tighter controls on their limits. In the case of lyophilized drug product, tighter control strategy may be required over the residual salts/impurities coming from the upstream and down stream processes of drug substance, the impurities in sugars (reducing sugars), the concentration of protein and weight ratios of stabilizer & bulking agent (mannitol and sucrose) depending upon the product and the process. All of these impact the collapse temperature/Tg’ of the final formulation, the physical state and intended role of each excipient in the formulation and finally the cake appearance and storage stability.
Drug Product Processes
Lyophilization
It is imperative to first understand the expectations from the lyophilization process and define the target process prior to its development and characterization to construct the design space. The process must be designed in such a way that it meets the predefined objectives i.e the product should look pharmaceutically elegant without collapse, has low residual moisture content, short reconstitution time, in-process retention of activity and adequate shelf-life. From the commercial manufacturing point of view, the process be short (i.e. economically viable and efficient), operative within the capabilities of the equipment with appropriate safety margins and efficient plant utilization and, finally the process should consistently and reproducibly operates within the established “Design Space”.
The development of the lyophilization process starts with the characterization of the frozen formulation to determine the freeze drying properties followed with the identification of process parameters. It should involve the utilization of the Prior-Knowledge and experience gained through the development of similar molecules with similar formulation composition and material manufactured for early stage clinical studies. During the development of the process one should also take into consideration the manufacturing challenges ahead, challenges relating to differences in environment (e.g. effect of particle free environment), differences in load size (scale related issues), differences in equipment (dryer) design, time and procedure differences etc.
The most challenging part of the freeze drying process is the construction of the “Design Space,” which is one of the key elements of QbD and requires thorough “Process Understanding” which means the CPPs controlling the variability in the CQAs be identified and understood during process development so that they can be measured and controlled in real-time during manufacturing process. One way of doing this is by using Prior-knowledge and riskbased assessment to list all the parameters that have the potential to influence the process performance and product quality attributes. They typically fall into four buckets (see Figure 1) a) Freeze drying process operating parameters (shelf temperature, chamber pressure, ramp rates and hold-times), b) Product parameters (protein concentration, excipients and their concentrations, vial configuration, stoppers, fill volume), c) Equipment (capabilities and limitations, batch load/size, scale effects), d) Components preparation and Devices. The variables from the first three buckets directly impacts the process performance and imposes boundaries on the “Design Space” while the variables from the fourth bucket not so much influence the process but impacts the product quality attributes. The next step is to design multivariate experiments supported with the stability studies to determine the degrees of impact each parameter has on the CQAs. This evaluation could be based on statistical significance in the experiments and, process parameters that significantly impact CQAs will be categorized as Critical Process Parameters (CPP) and those that are not but are important for consistency of the process performance or other business related factors are categorized as Key Process Parameters (KPP). The parameters or material attributes that are demonstrated to be influential and critical to the CQAs need to be further studied using DOEs involving multivariate combinations and interactions with other parameters to define the operating boundaries around the target within the design space. These studies can be performed using a scale-up model that mimics and represents the commercial scale freeze dryer conditions. The validity of the model and the operating space within the design space can be confirmed and demonstrated with a verification experiments at full scale. In order to have the understanding and data to support the non-conformances during commercial manufacturing, univariate studies can be performed and proven acceptable limits can be established but these do not constitute the design space.
Risk Assessment and Control Strategy
Initial assessments followed by experimentation with multivariate studies using appropriate scale models provide the understanding of relationship between the process parameters/ material attributes and product quality attributes and help identify robust process conditions and their acceptable limits. Priorknowledge coupled with product needs help establish product quality attributes specifications. The next step is to perform final overall risk assessment that will serve as the basis for the development of control strategy for commercial manufacturing of the product. Risk assessment should involve independent evaluation of each CQA and failure mode and effects analysis (FMEA) tool is commonly used to assess the severity of the failure, the probability of CQA going out of the acceptable range based on process capability and ability to detect it based on proposed in-process and lot release testing. Based on the scoring the proposed overall control strategy is refined to ensure the CQAs are within the acceptable ranges. The control strategy includes material controls (qualification & specifications of raw materials, excipients, drug active, packaging material etc.), procedural controls (equipment, facility, quality system etc.), process monitoring & controls (critical and key process parameters) and testing (in-process and lot release testing). Measurement and control of the critical parameters should integrate with a broad spectrum of analytical technologies interfaced to production plant control networks and assimilated into standard procedures. Various on-line and in-line tools provide the possibility of real time release. In the field of Lyophilization, few Process Analytical Techniques (PAT), such as Manometric Temperature Measurement (MTM), Tunable Diode Laser Spectroscopy (TDLAS), Near Infrared Spectroscopy (NIR), and wireless Product Probes are available. Manometric Temperature Measurement and TDLAS techniques have wider applicability relative to others and are capable of monitoring and measuring critical dependable variables (sublimation rate and product temperature at the sublimation interface) on the fly in addition to measuring primary drying end point, product resistance and moisture content. PAT helps to provide consistency to the process; improved quality, efficiency through reduction of cycle times and prevent product reject.
In conclusion, QBD entails quality target profiles, risk analyses, screening and optimization studies, scale up studies, and controlled strategies. Tremendous progress has been made in this paradigm for a lot of dosage forms, and lyophilized products should also be amenable to this strategy for enhanced product and process understanding..
References
1. Manning MC, Patel K, Borchardt RT. Stability of protein pharmaceuticals. Pharm Res., 1989, 6: 903-918 Pearlman R, Wang YJ. Formulation, Characterization, and Stability of Protein Drugs. (Series: Pharmaceutical Biotechnology, Vol. 9), Plenum Press, New York (1996) (ISBN 0-306-47452-2)
2. US Food and Drug Administration. Guidance for Industry. PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance. Pharmaceutical cGMPs. Rockville, MD; 2004 Sept. p. 1–21.
3. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach (Rockville, MD, Aug. 21, 2002).
4. ICH, ICH Q8: Pharmaceutical Development, Step 4 (Geneva, Nov. 10, 2005).
5. ICH, ICH Q8: (R1): Pharmaceutical Development Revision 1, Step 3 (draft, Geneva, Nov. 1, 2007).
6. ICH, ICH Q9: Quality Risk Management, Step 4 (Geneva, Nov. 9, 2005).
7. International Conference on Harmonization. Q10, Pharmaceutical Quality System. Geneva, Switzerland, 2007.
8. Guidance for Industry and Review Staff: Target Product Profile-A Strategic Development Process Tool, Draft Guidance, US Department of Health and Human Services Food and Drug Administration, March 2007.
9. Feroz Jameel and Mike Pikal “Design of a Formulation for Freeze Drying” chapter 18 in “Formulation and Process Development Strategies for Manufacturing of Biopharmaceuticals” Feroz Jameel and Susan Hershenson, editors, John Wiley & Sons, Inc. Accepted for publication, 2009
Dr. Mansoor A. Khan is the Director of Product Quality Research at CDER in FDA. Prior to joining FDA, Dr. Khan was a Professor of Pharmaceutics and Director of Graduate Program in the School of Pharmacy at Texas Tech University Health Sciences Center. He is a registered pharmacist, and has earned his Ph.D. degree in Industrial Pharmacy from the St. John’s University School of Pharmacy in 1992. He has published over 160 peerreviewed manuscripts, four texts including the “Pharmaceutical and Clinical Calculations”, eight book chapters, and more than 125 presentations in various meetings. As a major advisor, Dr. Khan graduated 10 Ph. Ds in pharmaceutics before joining FDA. Dr. Khan’s research focus is primarily in the area of pharmaceutical technology, excipient functionality, evaluation of critical formulation and process variables, drug delivery of challenging molecules, nanoparticles, Quality by Design and Process Analytical Technologies. He has held several leadership positions at the AAPS. He is an AAPS Fellow and currently serves as the FDD Chair. He serves on the editorial board of Pharmaceutical Technology, AAPS PharmSciTech, The International Journal of Pharmaceutics, and the Journal of Clinical Research and Regulatory Affairs.
Feroz Jameel, Ph.D, is a Principal Scientist in Drug Product & Device Development at Amgen Inc, Thousand Oaks, CA. He received his undergraduate degree in Pharmacy from Kakatiya University, Master’s degree in Pharmaceutics from University of Delhi and Ph.D in Pharmaceutics from University of Connecticut. He performed his postdoctoral work with Professor M.J Pikal where he was involved in the formulation and process design for freeze drying of various proteins, antibiotics and conventional small molecules. Some of this work led to granting of patent and served as basis for further development of protein formulations and lyophilization cycles of biopharmaceuticals. He received several awards including AAPS and PDA’s Fred Simon’s award. He has chaired several symposia on the development of biological products. In his current role at Amgen he is involved in the development, optimization, scale-up and transfer to manufacturing of formulation, filling and lyophilization processes for biopharmaceutical products.