Inspections by the FDA and foreign regulatory agencies have significantly increased since 2003 as manufacturing becomes more global and other countries regulate drug products. Between 2003 and 2005, the number of foreign inspections performed by the FDA ranged between 218 and 252. By 2007, that number had increased to over 450 per year and by 2009, it was up to nearly 550, dropping to 522 in 2010. In 2008, joint inspections began between regulatory agencies. That process continues today:
With the current leadership at the FDA stressing enforcement (as opposed to repeated warnings) for any violations or irregularities, 2010 saw the following actions:
As demonstrated by the data collected by EFPIA, Agency inspections in Europe hit their high point in 2009, then began to level out somewhat. We believe this leveling is due to the major, worldwide regulatory agencies reaching their inspectional resources limits. The FDA is still conducting the most inspections in Europe followed by the EU, then Brazil, South Korea, Japan and Mexico. Of concern to us is the ever-growing number of inspectorates conducting “foreign” inspections. And while China is not represented in the 2010 data, they are anticipated to become a major inspectorate in coming years.
As more and more countries begin implementing GMPs as a requirement for import, inspections of facilities in the US may continue to increase. However, Regulatory Agencies are also realizing that the number of manufacturing sites is growing faster, worldwide, than their resources available to perform inspections. We hope the number of inspections being performed will remain close to current levels.
Several factors make us think this will be true. For example, having the US FDA and other global inspectorates gain entrance to PIC/S will hopefully allow for better information-sharing between agencies, including inspection reports and resource sharing by inspectorates through joint inspections, one example being the recent EMA and FDA joint inspections which should reduce the number of on-site visits by Health Authorities.
At Enterey, in partnership with Mark Tucker, LLC, we can help you meet all your inspection management systems needs. This includes a system to help you self-identify and fully understand your compliance gaps; prioritize work and allocate resources to close those gaps; track gaps, actions taken and assess residual risk; fulfill the compliance requirements of ICH Q10; maintain an inspection-ready posture at all times; and respond to Agency findings systemically and quickly.
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FDA: NEW Guidance for Industry Process Validation: General Principles and Practices - Issued January 2011
FDA’s new guidance aligns process validation with the product lifecycle concept and ICH Guidelines Q8 (R2) Pharmaceutical Development, Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System).
The guidance encourages the implementation of modern development concepts of Quality by Design (QbD), such as design space, Quality Risk Management (QRM) and control strategy, throughout the product lifecycle.
The lifecycle concept links product and process development, qualification of commercial manufacturing process, and maintenance of the process in the state of control during commercial production.
The guidance supports process improvement and innovation through sound science and knowledge management.
Effective process validation contributes significantly to assurance of drug quality and that the drug produced is fit for its intended use.
The guidance defines process validation as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.
Process validation activities occur over the product and process lifecycle in 3 stages:
1 | Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
Process knowledge and understanding are obtained and captured during this stage. Studies should be conducted with sound scientific methods and principles and documented. Design of Experiment (DOE) studies help develop process knowledge. Risk analysis can be used to screen variables to minimize number of experiments while maximizing knowledge gained. Process information from product development can be leveraged in the process design stage and used in process qualification and continued process verification stages when the process design is revised or the control strategy changed.
The process knowledge and understanding gained at this stage form the basis for establishing a process control strategy.
2 | Process Qualification: During the process qualification (PQ) stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
PQ consists of 2 elements:
1) Facility design and qualification of equipment and utilities
2) Process performance qualification (PPQ).
Facility design and commissioning precede PPQ. CGMP procedures must be followed.
Completion of this stage is necessary prior to commercial distribution. If acceptable, products can be released for distribution.
The PPQ combines the actual facility, utilities, qualified equipment, and trained personnel with the commercial process under normal operating conditions.
A successful PPQ confirms process design and demonstrates commercial manufacturing process performs as expected. PPQ is based on sound science and manufacturer’s overall level of product and process understanding and demonstrable control. Higher level of sampling, additional testing, and greater scrutiny of process performance usually occurs during PPQ. The PPQ protocol is reviewed and approved by quality unit. The PPQ protocol execution and report, also reviewed and approved by all appropriate departments and quality unit, state a clear conclusion that the process is in a state of control.
3 | Continued Process Verification: During this stage, there is continual assurance that the process remains in a state of control (validated state) during commercial manufacture.
An on-going program to collect and analyze product and process data must be established. Data collected includes process trends and quality of incoming materials or components, in process materials, and finished products. Data should be statistically trended by trained personnel Production data is collected to evaluate process capability and stability. Continued process monitoring and sampling occurs at the level established during process qualification until sufficient data are available to generate significant variability estimates. Monitoring can then be adjusted to statistically appropriate and representative levels.
Knowledge and understanding gained is the basis for establishing an approach to control the process.
Manufactures should understand the sources of variation, be able to detect the variation, understand the impact of variation on the process and product, and control the variation commensurate with the level of risk to the process and product.
Controls can consist of material analysis and equipment monitoring at significant processing points.
Manufacturers of legacy products can benefit from knowledge gained from the original process development, qualification and experience. Legacy products and processes would likely begin with Stage 3 activities for continued process verification.
Homogeneity within a batch and consistency between batches are goals of process validation activities.
FDA recommends an integrated team approach to process validation with subject matter experts from process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance. Project plans and full support of senior management are necessary for success.Published by: Jim Anthony, Enterey | Director
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Up Next: What is different about the new process validation guidance? What should we be doing differently?
Tags: Life Sciences Industry News, Life Sciences News & Hot Topics, FDA New Guidance for Industry, Process Validation, ICH Q8, ICH Q9, ICH Q10, QRM, Quality Risk Managment, Process Verification, Process Qualification, Facility Design, CGMP, DOE, Quality Assurance, Drug Manufacturers
FDA: NEW Guidance for Industry
FDA issued its final guidance on Process Validation (Revision 1) on January 24, 2011. This guidance replaces the 1993 guidance.
This guidance reflects FDA’s current thinking on the topic and outlines the general principles and approaches that FDA considers appropriate for process validation for the manufacture of human and animal drug and biological products, including finished products, APIs, and combination products, and collectively referred to as drugs or products in the guidance.
This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance, including FDA / ICH guidances for industry Q8 (R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. Although this guidance does not repeat the concepts and principles explained in these guidances, FDA encourages the use of these development concepts, QRM, and QS at all stages of the product and manufacturing process lifecycle.
FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. Process validation for drugs is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B). CGMP regulations for validating pharmaceutical manufacturing can be found in 21 CFR Parts 210 and 211.
Although FDA guidance documents are recommendations, pharmaceutical manufacturers are already assessing the scope of the new guidance and performing a gap analysis to initiate corrective action and remediate the gaps in their current standard operating procedures to enhance and align their process validation activities with FDA recommendations.
Successful Process Validation in 3 Steps
Step 1: read the FDA guidance for industry documents.
Step 2: complete a gap assessment.
Step 3: determine an action plan via CAPA to correct the gaps and maintain the changes to your
process validation activities and Quality System.
Published by: Jim Anthony, Enterey | Director
Up next: Highlights in the new guidance document.
Tags: Corrective Action, FDA New Guidance for Industry, Process Validation, ICH Q8, ICH Q9, ICH Q10, Gap Analysis, Quality Risk Management, Pharmacautical Quality System, Steps to Successful Process Validation, CAPA