Knowledge Domain

Evolving Regulatory Expectations – are you in sync?

We start this series of articles with a brief backdrop on Pharmaceutical Regulatory Affairs.
History of medicines is older than start of Common Era; however, first pharmacopoeia appeared in Europe during 16th – 17th century. Unfortunate deaths of over 100 patients in USA due to poisoning by diethylene glycol used as a solvent in sulfanilamide elixir catalysed regulations of medicines. The pharmaceutical regulatory environment was strengthened further in 1960s after thalidomide episode in Europe. The awareness was spread across the world with WHO initiatives which eventually resulted in establishment of ICH in 1990. ICH brought in guidelines towards Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use.
In the initial phase the ICH guidelines spelled out regulations (Q1 to Q7). The focus on rule based regulations was shifted to the evolution of a knowledge base in the new millennium (Q8 to Q11) and more guidelines (Q12 to Q14) in this direction are in pipeline.
With introduction of Q8 to Q11 guidelines the rule based quality concepts of “standards” & “inspections” have been strengthened by principle based “Quality by Design” concepts.

The US Food and Drug Administration (FDA) released a new policy document (MAPP 5016.1) in May 2016. According to the new policy, reviewers should check applications to ensure that certain minimal elements described in ICH Q8(R2) –

  • Quality target product profile (QTPP),
  • Critical quality attributes (CQAs) of the drug product, drug substance and excipients,
  • Selection of an appropriate manufacturing process (QRM),
  • Control strategy

– are included in all applications

Other regulatory bodies also expect principles outlined in Q8 to Q11 are considered during development and manufacturing. Regulators now demand an understanding of product and process controls. Implementation of “Quality by Design” principles, as embodied in Q8 to Q11, is imperative.
Frequently the word design suggests a process to transform an idea into a product. In QbD, the process is conceptualized and developed (CMAs, CPPs identified) to meet product’s physico-bio-chemical characteristics (CQAs) which are derived from functional requirements (QTPP) which in turn depend upon patient needs (intended use = quality). A risk based approach to study sources of variability like RMs, process, environment (sanitation, lighting, humidity, temperature), packaging, storage, distribution and their impact on quality thus become part of development effort (Design).
In our opinion, many applicants put off implementation of QbD because of complex concepts like derivation of Design Space, RTR, use of PAT and DOE are associated with it. However, the biggest benefits of QbD can be attained by basic approach that involves identification of CQAs based on QTPP, linking CQAs to Process Variables (CMAs, CPPs) through use of QRM and use of data analytics to develop Control Strategy. With availability of statistical software to handle the demands of data analysis and DOE, the scientist needs only exposure to statistical concepts making the practice of QbD readily adaptable. The benefits of QbD are not limited to regulatory compliance alone but include well-structured development, process understanding, increased process capability, efficient scale-up, consistent performance and effective post approval change management.
To remain compliant with international regulatory environment, ‘Quality Management System’ adopted by a pharmaceutical company has to evolve in line with the emerging quality concepts. Follow upcoming articles in this series &/or contact us for structured sessions if you want to go in for QbD application.