Ajay Pazhayattil

A year’s worth of FDA warning letters suggest that API and finished drug manufacturers should strengthen their approach to continued process verification.

	In 2011, when FDA revised its process validation guidance (1), it introduced the idea that validation must continue throughout the lifetime of a pharmaceutical product. FDA advocated three stages:

		Process design, using the principles of pharmaceutical quality by design (QbD)

		Process performance qualification (PPQ)

	Pharmaceutical manufacturers have been developing novel methods and solutions to support this new definition of process validation, and FDA has been encouraging science- and risk-based approaches for all three stages.

	Other regulatory agencies have also embraced the lifecycle approach to process validation, including the International Council for Harmonization (ICH) in its Q8, Q9, and Q10 Questions and Answers (R4) (2) guidance for industry. ICH views the entire product lifecycle as: development, technology transfer, manufacturing, and discontinuation (3). 

	Best practices call for approaches such as:

		Taking a design-of-experiments (DoE) approach to product development, sampling, and testing plans

		Using data-driven statistical tools for CPV. 

	The European Medicines Agency’s (EMA) 2014 process validation guidance, the World Health Organization’s 2015 Appendix 7, and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) 2015 Annex 15 all reflect the expectation that process validation should continue throughout the lifecycle of the process. Pharmaceutical manufacturers would do well to take an integrated lifecycle approach to process validation that works across multiple markets. 

	As the industry’s approach to lifecycle-based process validation has evolved, some companies now divide Stages 1, 2, and 3 into the following: 

		Stage 1A – Product Development, Stage 1B- Scale Up

		Stage 2A – Equipment/System/Utility/Facility Qualification, Stage 2B – Process Performance Qualification

		Stage 3A–a heightened verification program for newly introduced molecules and Stage 3B-routine continued process verification.  Implementing the process validation lifecycle approach globally demands that pharmaceutical manufacturers be especially careful in selecting the most effective statistical tools and Stage 3 strategies (4).

	A good knowledge-management strategy is essential, starting from Stage 1 to Stage 3 of the process validation lifecycle. Scientifically identifying sources of variability requires a robust QbD-based product development program along with a Stage 3 CPV program that allows for continual gathering of product and process knowledge. 

	Process drifts, or times when the process fails to perform at its best, trigger identification of sources of variability, ensuring improved control and allowing for continuous improvement. Ongoing collection of product and process knowledge is required for continuous improvement, and also to improve the development process for similar products (5).

	This article asks how well pharmaceutical manufacturers have been addressing new process validation requirements by analyzing FDA warning letters (WLs) from 2017 to date. The goal of this study is to understand which parts of the process may need to be strengthened in order to improve regulatory compliance and minimize risk.

	Since the FDA process validation guidance is applicable to drug substances, drug products, and biologics, insights from WL assessments (6) can provide ample supporting evidence to justify an integrated approach to process validation.

	For this research, 85 FDA WLs issued in 2017 and 2018 were analyzed, 61 for 2017 and 24 for 2018. Inadequacies were found in both API and finished pharmaceutical facilities, but occurred mainly in finished pharmaceutical facilities, as outlined in 

	In 2017 and 2018 FDA warning letters, process validation issues were more frequently noted in finished pharmaceutical than in API manufacturing sites, with noncompliance increasing by 5% between 2017 and 2018.  Of the warning letters analyzed, 40% contained observations that were related to process validation. Since 2017, 29 finished formulations sites have been found to be noncompliant with process validation approaches, and the number of facilities that were out of compliance increased in 2018 (

	Approximately 20% of the API sites that received warning letters during the period under examination had problems that were related to PV noncompliance. Two of the five warning letters related to API sites cited inadequate process control monitoring, resulting in the inability to ensure stable manufacturing operations and consistent drug quality. 

	Regulators who had inspected the facilities identified the strong need for engaging a qualified consultant to assist the organization in meeting current good manufacturing practice (cGMP) requirements. Another warning letter cited inadequacies in the sampling plan during the PPQ stage. It highlighted the need for a statistically sound sampling and testing plan as stipulated in the PV guidance. 

	In addition, inspectors found that the manufacturer was not monitoring critical process parameters adequately. In a third API process-related observation, the regulator cited that the organization did not demonstrate adequate process understanding, which includes failing to consider operating parameters for critical operations. Regulators focus on all three PV stages during an inspection. In its inspection, FDA staff called for hiring external help, especially when the manufacturer could not implement the Stage 3 CPV program independently.

	In 14 warning letters, regulators noted the manufacturers should follow FDA process validation guidance for the process validation elements. Additional assessment revealed a consistent pattern. As the warning letters make clear, the following are very important in process validation:

		Having a data-driven and scientifically sound process-validation program that appropriately identifies sources of variability

		Performing process performance qualification studies

		Establishing an ongoing program for monitoring process controls to ensure stable manufacturing operations and consistent quality. 

	The problem that inspectors most often found at finished pharmaceutical facilities was failure to establish a continued process verification program to identify sources of variability.  This gap was cited in 17 warning letters. Eight of the citations pointed out that the manufacturer did not perform PPQ studies.

	Observations about Stage 3 CPV-related operations were found across prescription, over-the-counter (OTC), and sterile manufacturing sites alike. The regulator used consistent language and quoted from the 21 US Code of Federal Regulations (CFR) Part 211, Subpart F- Production and Process Controls, Sec. 100–Written procedures, deviation (a). The 21 CFR 211.100 (a) section states: “There shall be written procedures for production and process controls designed to assure that the drug products have the identity, strength quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit” (7).

	There were five instances in which regulatory inspectors noted a failure to prevent microbial contamination in sterile manufacturing, including lack of established procedures as well as inadequate validation of aseptic manufacturing processes and sterilization. The drug manufacturer is required to implement elements of cGMPs for sterile drug products using aseptic processing. Additional observations that were cited included deficiency in performing smoke studies for classified areas, which include Restricted Access Barrier Systems (RABS).

	For this assessment, warning letter trends were analyzed to provide manufacturers with some insight into regulators’ objectives. Both API and finished pharmaceutical manufacturing sites are consistently being cited for violating best practices in recent process validation guidance.  Analysis of the observations confirms the need for a well-defined continued process verification program that continually monitors the sources of variability and enables an organization to embark on continuous improvement initiatives prior to encountering quality issues. 

	Regulators around the world are encouraging the use of data-driven, science-based approaches to process validation. In some cases, inspectors have suggested that manufacturers enlist the help of qualified consultants, which will require that they invest time and resources in establishing a Stage 3 CPV program and supporting team. 

	More biopharmaceutical manufacturers are now striving for data-driven approaches to Stage 3 process validation, and solution providers are offering integrated software to help manage such programs. The convergence of regulatory guidance, current inspection trends, and the emergence of solutions allows existing monitoring programs to be enhanced, but there will likely be a need for additional elaboration and training across quality, operations, R&D, and regulatory functions. 

	Ensuring that process validation programs and training bridge different functional groups within the organization helps all groups understand their role in enabling continuous improvement. This kind of approach will help manufacturers prevent process failures, and can also help guard against having people overreact to individual events. It can also ensure that they catch sources of variability that might otherwise go undetected. 

: This article was prepared by the authors in their personal capacity. The opinions expressed are their own and do not reflect the view of their employer, government, or any agency with which they are affiliated.

Guidance for Industry: Process Validation-General Principles and Practices

, (Silver Spring, MD, Jan 2011).
	2. ICH, 

Q10 Harmonized Tripartite Guideline, Guidance for Industry: Q8, Q9 and Q10 Questions & Answers (R4)

(ICH, November 2010), ich.org.
	3. ICH, 

Q10 Harmonized Tripartite Guideline, Pharmaceutical Quality Systems

, September 2017.
	5. Parenteral Drug Association (PDA), “How Global Pharma Organizations Can Achieve Process Validation Success,” 

Warning Letters and Notice of Violation Letters to Pharmaceutical Compliance, Silver Spring, MD

Title 21, Food and Drugs, 21 Code of Federal Regulations 211.100(a)


	Supplement: Outsourcing Resources
	Vol. 42
	August 2018
	Pages: s22–s25

	When referring to this article, please cite it as A. Pazhayattil, N. Sayeed-Desta, and M. Ingram, “Lifecycle-Based Process Validation Emphasizes the Need for Continued Process Verification," 

Pharmaceutical Technology Outsourcing Resources Supplement

	Ajay Babu Pazhayattil is director, quality and compliance, at Eurofins Alphora Inc. (ajay.pazhayattil@alphoraresearch).He has held key management roles with brand name, generic, and contract manufacturing pharmaceutical organizations. Naheed Sayeed-Desta has experience in product development, technical services, and validation. Marzena Ingram has extensive quality assurance and technical operations experience. She developed a specialized continued process verification team and spearheaded the implementation of a product lifecycle program.

Articles

Lifecycle-Based Process Validation Emphasizes the Need for Continued Process Verification

Pharmaceutical cGMPs for the 21st Century, A Risk-Based Approach 

(1) provided the initial momentum needed to help promote collaborative efforts within the pharmaceutical industry. Designed to modernize pharmaceutical manufacturing and make it more efficient, the guidance highlights the importance of continuous improvement to improve efficiency by optimizing processes, reducing variability, and eliminating wasted effort.

	Reducing variability benefits both patients and manufacturers; therefore, regulators have voiced strong support for continuous improvement activities. For example, FDA and the International Council for Harmonization (ICH) support quality-by-design (QbD)-based product development. 

	QbD, advanced in ICH Q8 (2), focuses on the use of multivariate analysis in combination with knowledge management tools to understand the impact of critical material attributes and critical process parameters on drug product quality attributes. The heightened product and process understanding that result from using this framework provides a foundation for continuous improvement.


	Vol. 41, No. 8
	August 2017
	Pages: 40-42

	When referring to this article, please cite it as J. Collins et al., “A Continuous Improvement Metric for Pharmaceutical Manufacturing,”

Statistical methods and novel indices can be used to monitor and benchmark variability, and guide continuous improvement programs in late-stage drug development.