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The authors provide an overview of the new ISPE Guide Series on Product Quality Lifecycle Implementation and how the guides can be used in a complementary way with existing guidance from FDA and the International Conference on Harmonization.
The International Society for Pharmaceutical Engineering (ISPE) has released the first two parts of the ISPE Guide Series: Product Quality Lifecycle Implementation (PQLI) from Concept to Continual Improvement. These guides provide a practical approach to implementation of International Conference on Harmonization (ICH) guidelines on pharmaceutical development, quality risk management, and the pharmaceutical quality system, as well as FDA guidance produced under the Pharmaceutical CGMPs for the 21st Century Initiative, including guidance on process analytical technology (PAT) and quality systems (1–6). More recently, FDA published guidance on process validation (7); the ISPE series also provides information and assistance to meet Stage 1 (Process Design) of this guidance.
The ISPE Guide series is intended to assist and be a reference for practitioners involved in development, implementation, and application in manufacturing, including those involved in continual improvement. The suggestions, information, and examples presented in Parts 1 and 2 of the series have been derived from input from a wide range of companies and individuals who have hands-on experience of successfully applying enhanced, quality-by-design (QbD) approaches.
Part 1 of the ISPE Guide, Product Realization using QbD: Concepts and Principles, provides an overview of the series and a summary of enhanced, QbD approaches to development, including an introduction into manufacture and continual improvement of products and processes. It also provides a practical discussion and examples of of criticality, design space, and control strategy, which are addressed in ICH Q8 (R2) (1).
Part 2, Product Realization using QbD: Illustrative Example, offers a case study of the application of enhanced, QbD approaches to product realization. Part 2 addresses the development and introduction into manufacturing of a small-molecule formulation and associated manufacturing process, as well as part of the drug-substance synthetic route using enhanced, QbD approaches. Compared with other case studies in the public domain, more detail is given about the application of systematic, iterative, and different approaches to product and process understanding using quality risk management.
Parts 1 and 2 provide a range of how-to tools for practitioners developing products and their manufacturing processes using the enhanced, QbD approach described in ICH Q8 (R2). These guides provide more insight than is given in the ICH guidelines, and include more explanation and examples of individual topics, such as criticality as applied, for example, to critical quality attributes and critical process parameters (CQAs and CPPs), design space, and control strategy.
The concepts in the ISPE Guide series apply to both new drug products and existing marketed products. The authors believe that the principles also apply to drug-substance (small and large molecule) process development and continual improvement.
The concepts and examples developed reflect some of many optional approaches available to use QbD in pharmaceutical development and its effect on product realization.
Different activities in the product lifecycle are addressed in the series. Parts 1 and 2 focus on product realization using QbD. Other parts to be published address activities later in the product lifecycle, such as process performance and product quality monitoring system, change management, and selected elements of the process-validation lifecycle.
The series uses ICH terminology and the ICH guidelines Q8, Q9, and Q10, as well as Q11 on the development and manufacture of drug substances as a basis, together with other relevant ICH guidelines, questions and answer documents, and points-to-consider documents (8–11).
The need for guidance. Feedback from many sources indicates that practitioners want clear explanations and examples to demystify the concepts discussed in ICH Q8, Q9, and Q10, including "criticality" as applied to CQAs and CPPs, and "control strategy." Both terms have been used in the industry and "critical" has been used in many guidelines globally. "Design space" is a concept introduced and defined in ICH Q8 (R2).
ICH does not define "critical" even though the word is used extensively in its guidelines. ICH Q8 (R2) does offer definitions for CQA and CPP. Although the phrase "level of criticality" is not used and "critical" is not defined, there is general agreement within industry that assigning criticality to an attribute, parameter, or variable can be relatively subjective and dependent on context. Although a critical attribute or parameter is frequently interpreted as being high risk, what "high risk" means from a regulatory perspective remains debatable and inconsistent from company to company. Consequently, "criticality" is considered related to risk; therefore, this topic in the series addresses the application of quality risk management, based on ICH Q9, to the assignment of criticality.
"Control strategy" is defined in Q8 (R2) and Q10. How to establish a control strategy and its relationship to CGMPs and a pharmaceutical quality system is not discussed in sufficient detail for practitioners, particularly when some elements of a control strategy are derived from enhanced, QbD approaches, for example, when introducing real-time release testing (RTRT) or when PAT tools have been used. Suggestions are given to practitioners in Part 1 of the ISPE Guide and exemplification in great detail is provided in Part 2 to show how different elements of a control strategy combine to assure compliance with CQA acceptance criteria. In particular, Part 2 helps readers understand how:
"Design" space is a relatively new topic and, in response to many questions, guidance is given on the many ways in which design space can be developed, communicated, and maintained as part of product realization. A number of specific examples are given to assist the practitioner in understanding and being able to develop design spaces.
Benefits of an enhanced, QbD approach
Using the enhanced, QbD approach as discussed and exemplified in the PQLI Guides, Parts 1 and 2 has been shown in the development of new products to produce benefits of:
Although investment in QbD typically occurs in development and the benefits are reaped in manufacturing, there is considerable value to the business. Some examples are discussed below.
A product developed using QbD principles was showing 0.7% deviation rates in the first year of launch compared with two other products launched about 15 years earlier using the traditional approach with some continual improvement, which had deviation rates in a range up to 8% (12). As a further example, a product developed using QbD principles showed CQA of Assay PpK at launch of 1.2 (3–4σ) which rose to a PpK of 1.8 (5–6σ) six months postlaunch. Due to a well-developed design space, a site was able to increase productivity by 66% by optimizing process parameters within a design space and without regulatory filing when demand was four times its forecast.
In another example, development of a product leading to real time release testing gave a pay back of about one year with reduced throughput time and associated reduced inventory costs, and with a reduction in laboratory quality control costs.
Significant business benefits also have been reported in applying the enhanced, QbD approach to continual improvement of existing products (13). These benefits include increased yield, reduced variability, and decreased throughput time leading to decreased inventory levels, increased assurance of success of batch release. There also was some flexibility in regulatory commitments in terms of reduced stability studies and a different approach to process validation. Other benefits are suggested in the ISPE Guides.
It is considered that the guides can be of assistance in developing products and processes in line with Stage 1 (Process Design) of the FDA process validation guidance allowing rational selection of attributes and parameters and associated acceptance criteria for inclusion in Stage 2 (Process Performance Qualification) of the guidance (7).
Although proposing a design space is optional, extremely convincing justifications with examples are given in Part 1 for the benefits of developing and proposing a design space.
Key points from the guides
The workflow given in the ISPE Guide series is based on a schematic developed by an EFPIA team (see Figure 1) (14). Although Figure 1 suggests the workflow is linear, there is much discussion and exemplification to indicate that the work is more likely to be iterative, particularly the process development step of sequential and iterative application of quality risk management and design of experiments (DoE) studies. There are many detailed examples of quality risk assessment exercises linked to DoE studies in Part 2, with the output of a DoE study cycling back into another risk-assessment exercise to demonstrate reduction and eventual acceptance of risk.
Figure 1: Product realization using a QbD approach. DoE is design of experiments. CPPs is critical process parameters. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
How to assign criticality is discussed, the concept of a continuum of criticality based on risk assessment is suggested with examples. For CQAs, criticality is shown based solely on severity of harm (i.e., safety and efficacy) as linked to the patient through the quality target product profile as indicated in ICH Points to Consider document (10). For CPPs (and CQAs), the flowchart shown in Figure 2 indicates how quality risk-assessment steps can lead to a continuum of "criticality" based on severity, probability, and detectability. Many examples are given, such as types of risk assessment criteria with detailed discussion and explanation.
Figure 2: Process parameter continuum of criticality. CQA is critical quality attribute. PP is process parameter. RPN is risk priority number.
Design space is represented pictorially in Figure 3. Multifactorial relationships in the middle box in Figure 3 can be based on mechanistic understanding or first principles, or empirical, or hybrid models as represented in Figure 4.
Figure 3: Representation of design space as inputs and outputs.
There are discussion and examples of derivation of different types of design space, some not requiring DoE experimentation when they are based on first principles, in the ISPE series. With this relatively new concept of design space, the ISPE guides describe how to use design space in operation of flexible processes, how to consider the impact of scale and link of design space to control strategy, and how to update and continually improve a design space.
Figure 4: Commonly used model types.
Because development and operation of a control strategy is mandatory, significant attention is given in both parts of the series to development, choice, implementation in manufacturing, link to process validation, and continual improvement of control strategy. In Part 2, particularly, linkage of drug-substance control-strategy elements (e.g., particle size to drug product CQAs impacting patients), dissolution and uniformity-of-dosage-units tests are shown, including how to develop an algorithm in which drug substance particle size determined by in-line measurement in a high shear wet milling unit operation is a major, but not only contributor to predict dissolution values. Knowledge of drug-substance particle size can be used in a feed-forward manner to determine some relevant process parameters (e.g., lubrication time to assure the dssolution CQA acceptance criteria are achieved). Prediction of dissolution values is one element of a complex control strategy, the elements of which are derived from the enhanced, QbD approach discussed. Required CGMP elements also contribute to the control strategy and examples are given.
A summary of some elements of a control strategy leading to real time release is given in Figure 5 in comparison with a traditional approach. Figure 5 shows that RTRT usually involves more analysis (in-line, online, or at-line) compared with a traditional end-product testing approach coupled with, for example, in the application of fixed process parameter ranges.
Figure 5: Summary of some PAT elements of a real-time release testing scheme.
In response to ICH and regulatory guidelines, a group of experts representing the industry who have successfully prosecuted enhanced, QbD approaches to development and manufacture of drug substances and drug products have produced for ISPE two parts of a guide series on product realization. These guides can serve as learning material for practitioners and be a reference of relevant information.
Bruce S. Davis is a principal, Global Consulting; Ranjit R. Deshmukh, PhD, is senior director of Corporate Technical Science, MedImmune; John V. Lepore, PhD, is senior director, Chemical Process Development and Commercialization, Merck & Co Inc.; Line Lundsberg-Nielsen, PhD, is a senior consultant, NNE Pharmaplan; Roger Nosal is vice-president, Global Chemistry, Manufacturing & Controls, Pfizer, Inc.; Stephen M. Tyler is director, Analytics and Technical Projects, Abbott Laboratories; and Christopher Potter, PhD*, is a CMC Pharmaceutical Consultant.
*To whom all correspondence should be addressed.
Note: The ISPE Guide series is available at www.ispe.org.
1. ICH, Q8(R2) Pharmaceutical Development (August 2009).
2. ICH, Q9 Quality Risk Management (November 2005).
3. ICH, Q10 Pharmaceutical Quality System (June 2008).
4. FDA, Guidance for Industry: Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach (September 2004).
5. FDA, Guidance for Industry: PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (September 2004).
6. FDA, Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006).
7. FDA, Guidance for Industry: Process Validation: General Principles and Practices (January 2011).
8. ICH, Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), Step 2 (May 2011).
9. ICH, Q8, Q9, and Q10 Questions and Answers, Rev. 4 (November 2011).
10. ICH Quality Implementation Working Group, Points to Consider, ICH-Endorsed Guide for ICH Q8, Q9, and Q10 Implementation, Rev. 2 (December 2011).
11. ISPE Guide Series, Product Quality Lifecycle Implementation (PQLI) from Concept to Continual Improvement, www.ispe.org/index.php/ci_id/33025/la_id/1.htm.
12. J. Lepore and R. Nosal, R. "Industry Perspective: Value Proposition for Applications of Risk-Based Approaches," presented at ISPE Brussels Conference (2011).
13. C.J. Potter, Jrnl. of Pharma. Innov. 1:4–23 (2009).
14. EFPIA, www.efpia.org (Publications/Science and Technical Affairs.)