Quality by Design: Part 2

Coda dedicated last month’s installment of the blog to review initiatives undertaken by the Food and Drug Administration that were developed in order to improve regulatory strategies, and agency systems and tools.  The improvements we highlighted, among others, were developed and implemented in the hopes of contributing to industries’ efforts to develop new and safe therapies as quickly as possible and for as many portions of the population as possible, and as inexpensively as possible.
We also provided an overview of one of the most dramatic initiatives proposed by FDA, one offering incentives to adopt enhanced
approaches to pharmaceutical development, allowing use of statistical, analytical, and risk assessment methods. This initiative was referred to as “Quality by Design” (QbD).  FDA, through QbD, hoped to incentivize manufacturers to strengthen their control systems in design space, by offering them the ability to propose regulatory and approval schemes as long as the approach they suggested was data driven
and was developed to manage consumer-centric risk.
Amid concerns that use of QbD strategies would not satisfy European licensing efforts, FDA and European Medicines Agency
(EMA) launched a pilot program that would allow manufacturers to submit a single CMC package to a review panel that represented both agencies prior to preparing an entire NDA, allowing participating manufacturers to have the quality and CMC data reviewed in parallel by both agencies. 
It was hoped that the pilot program, scheduled to open in 2011 and close in 2014, would attract a large volume of participants as the companies involved were also promised direct communication with the regulators, allowing any issues to be addressed prior to final preparation of the entire licensing packages.
Recently, the joint panel issued a public document, reviewing progress of the program and responding to industry’s questions.  The public statement opened with this encouraging report:


We have reviewed the document and are presenting the Q&A in this month’s installment, supplemented by our review comments.  Coda’s
comments have been presented in italics for visibility.
What are the Agencies’ expectations in a regulatory submission for Quality Target Product Profile (QTPP)?
Panel Answer:
The Agencies’ expectation is that applicants will provide the QTPP, which describes prospectively the quality characteristics of a drug product that should be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. The QTPP is specified only for the finished product. Although there is no special format to provide the QTPP information, it would be useful to present in a tabular format in the application.
What are the Agencies’ expectations in a regulatory submission for Critical Quality Attributes (CQAs)?
Panel Answer:
The Agencies’ expectation is that applicants will provide a list of CQAs for drug substance, finished product, and excipients when relevant. This list should also include the acceptance limits for each CQA, and a rationale for designating these properties as a CQA. Furthermore, there should be a discussion of how the drug substance and excipient CQAs relate to the finished product CQAs based on prior knowledge, risk assessment or experimental data. The basis of the control strategy should be to ensure that the drug substance and finished product CQAs are consistently within the specified limits.
Although there is no special format to provide information on CQAs, it would be useful to present in a tabular format in the application.
Would the Agencies accept a three-tier classification of criticality for process parameters?
Panel Answer:
In accordance with ICH Q8(R2) a critical process parameter is one whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
In a submission that was evaluated by both EMA and FDA, the Applicant proposed an approach to risk assessment and determination of criticality that includes a three-tier classification for quality attributes and process parameters: critical, key and non-critical. In this
approach, a critical factor was defined as a factor that led to failure during experimentation. A factor that had not led to failure within the range studied, but still may have an impact on product quality, was considered as a key factor.
The Agencies do not support the use of the term Key Process Parameters (KPP) since it is not an ICH terminology. Furthermore, experience reveals that different applicants use the term “key” differently, leading to more difficult internal communication. The fact
that a risk of failure is mitigated by applying a robust proactive control strategy should not allow for the underestimation of assigning criticality. The Agencies are amenable to the applicant using this terminology in the pharmaceutical development section to communicate development findings.  However, in the “Description of the Manufacturing Process and Process Controls” and “Control of Critical Steps and Intermediates” sections, the description of all parameters that have an impact on a CQA should be classified as critical.
What are the Agencies’ expectations in a regulatory submission for manufacturing process descriptions?
Panel Answer:
The same requirements apply to the level of detail in the manufacturing process description irrespective of the development approach. For US FDA, a comparably detailed process description can be submitted in lieu of a Master Production Record for drug product manufacturing for 505(b)(1) products. However, proposed or actual commercial scale Master Production Records are required for generic and 505(b)(2) products. In EU, there is requirement for a full description of the manufacturing process in all cases.
It is important that the process descriptions be comprehensive and describe process steps in a sequential manner including batch size(s) and equipment type. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. Steps in the process should have the necessary detail in terms of appropriate process parameters along with
their target values or ranges. The process parameters that are included in the manufacturing process description should not be restricted to the critical ones; all parameters that have been demonstrated during development as needing to be controlled or monitored during the process to ensure that the product is of the intended quality need to be described.
General comment regarding the concepts defined in ICH Q8(R2) in the area of analytical methods:
Recently, industry has been applying QbD concepts in the area of analytical methods using risk assessments and statistically designed experiments to define Analytical Target Profiles (ATP) and Method Operational Design Ranges (MODR) for analytical methods. The ATP and MODR parallel the Quality Target Product Profile (QTPP) and Design Space defined for a manufacturing process.
There is currently no international consensus on the definition of ATP and MODR. Until this is achieved, any application that includes such proposals will be evaluated on a case-by-case basis.
What are the Agencies’ views with respect to the use of analytical target profile (ATP) for analytical methods?
Panel Answer:
In general, an analytical process profile (ATP) can be acceptable as a qualifier of the expected method performance by analogy to the QTPP as defined in ICH Q8 (R2).  However, the Agencies would not consider analytical methods that have different principles (e.g., HPLC to NIR) equivalent solely on the basis of conformance with the ATP. An applicant should not switch between these two types of methods without appropriate regulatory submission and approval.
What are the Agencies’ expectations in regulatory submissions for Method Operational Design Ranges (MODR)?
Panel Answer:
Similar principles and data requirements described in the ICH Quality Working Group Points to Consider (R2), Section 6 “Design Space” could apply for MODRs. For example, data to support an MODR could include:
(a) appropriately chosen experimental protocols to support the proposed operating ranges/ conditions; and
(b) demonstration of statistical confidence throughout the MODR.
Issues for further reflection include the assessment of validation requirements as identified in ICH Q2(R1) throughout the MODR and confirmation of system suitability across all areas of the MODR.
The initial response we had when we reviewed the document, was that it was brief, and lacked any data regarding the number of applications processed, the number of approvals granted, or metrics regarding application to approval cycle time.  Also notable, was the specificity of the questions and the precision of the answers.
Including metrics would have suggested demand for inclusion in the program, ready alignment of the agencies, and time to approval improvements. 
Questions regarding concepts and the paradigm shift would have indicated the scope of change the applications received under this program represented.
However, as this was the panel’s first joint and public reflection of progress, the type of questions included seem to suggest that these details may have been points of contention either between the applicants and the panel, or perhaps, between the two (2) agencies?
Brevity aside, the key points were these:
  • The ICH terminology is a point of serious alignment – if you haven’t already adopted the glossaries from the ICH Guidelines into your corporate lexicon – you should do so – right away
  • Submitting Quality Target Product Profiles (QTPPs) does NOT remove the need to define, describe and submit Critical Quality Attributes (CQAs)
  • Don’t call anything a Key Process Parameter(KPP) – neither agency is going there – and they gave us a not so gentle reminder – DON’T invent your own language
  • Developing your own design and validation strategies does not mean that we can abbreviate the process descriptions required by the CMCs, so don’t get rid of those templates just yet
  • Analytical Method Development and Validation are still confusing spaces for everyone, on which the agencies do not agree. Compliance guidance in these spaces for the time being will remain in the form of “You show us what you did, and we’ll tell you what we think about it.”
  • Stay away from the word equivalence – just don’t go there – when it comes up in compliance advice giving documents,  it never fares well.  
  • If you manufacture sterile products – validate everything, every single thing.


Applications for submission will continue to be accepted through March 2014, and the panel promises to issue additional statements on “other QbD-related topics” as the pilot project continues with new batches of parallel assessments.
However, as close to 75% of the program time line has already expired, it seems unlikely that this program will produce substantial guidance for industry, although perhaps it will be enough time to produce substantial alignment between the agencies.
What does seem likely?  That meaningful compliance guidance on QbD topics that make up some very big spaces will not be issued until there is very meaningful alignment.  Members of industry continue to try to assess models for these QbD programs, but may not
implement them until they see hard evidence of compliance.  This may apply to programs such as:
Design Space Verification
Design Space and Risk Assessment detail required
for submissions
Continuous Process Improvement Verification
Continuing Validation and Re-Validation
If QbD practices are to be adopted and truly effect approval cycle time, industry will need to fully understand the regulators expectations with regard to these spaces and the data they produce.  We at Coda hope to see meaningful guidance on these topics issued quickly, so that they potential benefits of this initiative can be realized for industry, and every American citizen.
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Authored By:
Gina Guido-ReddenChief Operating OfficerCoda Corp USA

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“Quality is never an accident; it is the result of high intention, sincere effort, intelligent direction and skillful execution. It represents the wisest of many alternatives.”
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