Battling non-conformance to quality

Michael Payne, Principal Technical Consultant, Process Solutions, Merck elaborates on the need to evaluate the quality systems in pharma organisations and plug the gaps to reduce non-conformance and risk

Michael Payne, Principal Technical Consultant, Process Solutions, Merck elaborates on the need to evaluate the quality systems in pharma organisations and plug the gaps to reduce non-conformance and risk

20160531ep51Some of the possible causes of non – conformance include lack of a robust quality culture, low maintenance of an effective quality system, lower investment in quality, an increased focus on immediate financial aspects of pharma manufacturing, overestimation or overconfidence in the quality system, ineffective implementation of process analytical technologies, and a lack of understanding of the benefits of learning from other manufacturers inspection experiences around the world.

By reviewing the roles and activities of regulators, the foundations of modern-day quality systems, quality by design and quality risk management, and some the information available about inspectional observations and trends, this article will hopefully provide fuel for thought and a stronger appreciation of a robust and effective quality system that reduces risk and increases conformance.

Role of the regulator

The regulator is the agency responsible for the protection of the health of the public whose government the regulator represents. As such they have an inherent interest in many areas like:

Development of new and innovative medicinal products, medicine and healthcare product manufacturing, distribution of medicines and helping to ensure the continued supply of medicines and healthcare products now and in the future.

An example of the charter of a regulatory agency is the UK MHRA which states1 that the agency “regulates medicines, medical devices and blood components for transfusion in the UK. The agency is responsible for: ensuring that medicines, medical devices and blood components for transfusion meet applicable standards of safety, quality and efficacy, ensuring that the supply chain for medicines, medical devices and blood components is safe and secure, supporting innovation and research and development that’s beneficial to public health.”

Similarly, the US FDA states2 that it is “responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. FDA is also responsible for advancing the public health by helping to speed innovations that make medicines more effective, safer, and more affordable”.

The desire for cost effectiveness however cannot reduce the five critical aspects of drug products and substances: efficacy, strength, safety, quality and purity.

Regulatory support for industry improvement

Over the past 15 years, regulatory agencies such as the US FDA have actively encouraged and cajoled the industry to move away from the exclusive use of traditional equipment, tools, methods and approaches towards the incorporation of new production and analytical technologies and risk assessment concepts.  This was to support the industry in driving down the cost of non – conformance and reducing patient risk.


In 2004, the US FDA published3 ‘Pharmaceutical CGMPs for the 21st Century – a Risk Based Approach’ with the desired objectives including the encouragement of the pharma industry to adopt new technological advances, the application of modern quality management techniques, the implementation of quality systems and of risk-based approaches. At the same time, the document was to help ensure that the US FDA’s regulatory review, compliance, and inspection policies would be based on state-of-the-art pharma science.

Two years later Dr Janet Woodcock4 gave the US FDA’s view of the desired direction of the pharma industry when she said that the desired state is ‘a maximally efficient, agile, flexible pharma manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight’.

Now over 10 years later, the major regulatory agencies have adopted ICH guidelines including ICH Q8 (Quality by design and the design space concept), ICH Q9 (Quality Risk Management) and ICH Q10 (Robust Quality Systems). The concept of quality by design (QbD) is a ‘systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management’.5

The four design spaces can be seen in the figure shown above. Since there is data collected by the drug substance or drug product manufacturer during the development and scale-up phase, the design space delineates the boundary where the product or substance has known efficacy/ safety/ purity/ strength and quality. If the manufacturing process accidentally drifts outside the control space, there is no need to raise a change since working within the design space is not considered to be a change. This reduces the risk to the patient, and reduces the incidence of product or substance non-conformance.

Risk management and effect on validation

The principles of quality risk management (QRM) is present in regulatory guidelines such as ICH Q9, EMA volume 4 Annex 20, WHO Guideline on Quality Risk Management, etc. along with a number of industry and research association documents.

One of the outcomes of the combination of a quality risk management approach and a quality by design approach is that traditional validation concepts are challenged.  The idea of three sequential qualification runs is not considered to be based on science. With QbD principles, a different number of runs may be required to show that the process is operating in the defined control and design space.  The same principle does not require operation at a predetermined set of specific datapoints and so a triplicate set of moist heat sterilisation operations at (say) 126oC may not prove the robustness of the sterilisation process.

Similarly, a demonstration of a process based on the understanding at time process was developed and ‘finalised’ is not as robust as the collection and analysis of data from proactive and iterative activities throughout the process lifecycle. In a traditional approach, a deviation is seen as a setback and in certain less robust quality organisations is can be something to be explained away.  With the increase in analytical tools, understanding of the effect of raw material and process variability, a deviation can provide an opportunity to increase process understanding and avoid failures later on during commercial manufacturing.

Change drivers

There are a variety of drivers that can trigger the need to re – evaluate pharma production processes, risks and the robustness of the company’s quality system. These include:

  • Results of regular internal reviews and self-audit programmes
  • Product annual or product quality review
  • Routine SOP revisions and updates
  • Change controls
  • Changes in national or international regulations
  • A change in the national inspector training process
  • External reviews from potential technology transfer partners
  • Regulatory/ compliance/ licensing inspection results
  • Preparation for regulatory inspection

These reinforce the concept of current GMPs (cGMP) versus GMPs and support the company’s focus on maintaining quality, reducing risk, achieving acceptable cost of goods, reducing non-conformance and reducing patient, product and company risk.

Learning from others – Regulatory inspection trends

As mentioned above, one of the change drivers is the information available from MHRA, PICS, and US FDA about warning letters, inspectional observations, compliance trends etc. Much of this can be accessed on the internet using regulatory sites such as the FDA Inspection Observations.

At least one large contract manufacturer uses the inspectional observations as a continuous learning tool for the personnel in their facilities. Each relevant observation is sent out via email so that all production, quality, engineering and facilities personnel can see what has been reported and so trigger attention to the possibility of the same issue occurring in their facility.  Actions like this ensure that cGMPs, continuous improvement, quality ownership and the maintenance of a quality culture are in everyone’s mind.

The most recent inspection data available from the MHRA is from 20136. The top 10 areas of deficiency is shown in Table 1.



An example of inspection trends can be seen in a comparison of FDA observations from 2014 and 20158. (Check Table 3).


As can be seen, the relative percentages are consistent across the two years with the exception of a significant increase in the number of observations in the design and construction aspects of buildings and facilities.

An unbiased and open review of information is of real benefit to companies seeking to practice continuous quality improvement, reduce inspection observations and to reduce patient and product risk. This information should not be used as a ‘checklist’ with the purpose of showing that the current procedures and practices are acceptable. Each observational category should be reviewed by a multidisciplinary group of employees with the idea that these areas will be openly assessed with an unbiased view, since this approach is most likely to generate the greatest increase in learning and in potential quality and risk improvement.

Example of stronger future focus – Data integrity

A review of information from the FDA, EMA and PICS shows that data integrity was flagged as an area of concern as early as 2008 as a result of inspections carried out in North America, Europe and the rest of the world. All regulatory agencies have found evidence of data integrity issues including:

2012 WHO prequalification inspections that found evidence of incorrect and inconsistent data manipulation, data falsification, and raw data that was lost or destroyed.9

2013 PICS7 reported finding inspection deficiencies such as:

  • recording data in logbooks, falsification of batch records and test results, pretesting samples and ignoring or not investigating out-of-specification results,
  • blending or mixing batches that failed to meet the established released specifications with batches that met the required final specifications,
  • ineffective controls in handling and managing critical data, and entering manufacturing activities on records before they had occurred.

In 2013 the MHRA announced10 that they were ‘setting an expectation that pharma manufacturers, importers and contract laboratories, as part of their self-inspection programme must review the effectiveness of their governance systems to ensure data integrity and traceability. This aspect will be covered during inspections from the start of 2014, when reviewing the adequacy of self inspection programmes in accordance with Chapter 9 of EU GMP.’

This information is very valuable for relevant pharma manufacturers to allow them to check and if necessary correct data handling practices, quality systems and shortcomings in quality culture.


Inspectional observations and trends can provide a valuable source of material to help pharma companies reduce non – conformance, increase efficiency, reduce costs and strengthen their quality systems. Newer approaches such as process analytical technologies, quality by design, quality risk management, and quality metrics can be used to ensure that procedures and products maintain a high level of safety, purity, efficacy, and strength.


4. Janet Woodcock, M.D.  – CMC Workshop (October, 2005)
5. ICH Q8\downloads\Drugs\Guidances\ucm073507.pdf

Get live Share Market updates and latest India News and business news on Financial Express. Download Financial Express App for latest business news.