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The FDA’s draft Process Validation guidance – an industry review

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★ The 3-stage lifecycle approach to process validation is described in FDA’s recently published draft Guidance for Industry ★ This article provides a review of the guidance with particular emphasis on its impact on the current industry approaches to sciences and risk based design and qualification

by Nuala Calnan and Alice Redmond

ovember 2008 saw the draft publication of the FDA’s long anticipated Guidance for Industry on ‘Process Validation: General Principles and Practices’.1 It outlines the FDA’s current thinking on process validation for the manufacture of Human and Veterinary drugs including Biologicals and APIs.

Basic Principles The basic principle of quality assurance is that a drug should be produced that is fit for its intended use; this principle incorporates the understanding that the following conditions exist:

The Lifecycle Approach:

★ Quality, safety, and efficacy are designed or built into the product. ★ Quality cannot be adequately assured merely by in-process and finished-product inspection or testing ★ Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications.

The guidance states at the outset that it has been written to promote ‘modern manufacturing principles, process improvement, innovation, and sound science’ and is aligned with the Product Lifecycle approach described in the ICH Guidance Q8, Q9 and Q102. The lifecycle concept describes the importance of the links between product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. From this, the guidance defines a 3-stage process for Process Validation; Resulting in a new definition of Process Validation (PV) as:

‘The collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products’

Process Validation

1 Stage 3: Continuous process verification

Stage 1: Process design

3

2

Stage 2: Process qualification

Figure 1: Process Validation activities shown in three stages

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The FDA’s draft Process Validation guidance

alignment with current industry thinking for implementation of science and risk based approaches and where the most significant departures from the prescriptive approaches of the 1987 guidance are noted. Under ‘General Considerations for Process Validation’ it emphasizes the importance of making the entire process validation program more effective and efficient through the use of:

3 Stages of Process Validation ★ Stage 1 – Process design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities. ★ Stage 2 – Process qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. ★ Stage 3 – Continued process verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

★ Good project management and robust scientific knowledge management ★ Uniform collection and assessment of information about the process which should seek to reduce the chance for redundant information gathering and thereby enhance the accessibility of such information later in the product lifecycle ★ Process Simulation ★ An integrated team approach that includes expertise from a variety of disciplines ★ Project plans ★ The support of senior management.

Key tenets of the lifecycle approach are:

★ A successful validation program depends upon information and knowledge from product and process development ★ This knowledge and understanding is the basis for establishing an approach to control that is appropriate for the manufacturing process. It emphasizes the importance of process control, pointing out the importance of both QA professional and the line operator in providing feedback and continued process verification ★ The need for ongoing data analysis, within and between production batches ★ Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product ★ Emphasising that effective process validation contributes significantly to assuring drug quality

Outlined in this section is the strongest alignment of the ASTM standard E2700-07 and the draft PV guidance document. It strongly endorses the move away from ineffective or overly bureaucratic traditional qualification practices. ‘Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and should be approved in accordance with the established procedure appropriate for the stage of the lifecycle’

In the section entitled ‘Specific Stages and Activities of Process Validation in the Product Lifecycle’ the guidance returns to the three stage cycle proposed for PV and gives specific direction on each stage as to the recommended activities to be included.

Not surprisingly the guidance focuses on the importance of demonstrating and using process understanding in designing effective processes and their associated validation programs. It provides a strong lead in acknowledging that qualification programs devoid of process understanding will not guarantee the assurance of quality required.

Stage 1: Process design

The stated goal of this stage is to ‘design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes (CQAs)‘. The guidance again makes reference to ICH Q10, Pharmaceutical Quality Systems and draws some distinctions around the varying levels of controls required related to the product development lifecycle

Significant recommendations

The main body of the guidance comes under section IV Recommendations, where useful general considerations on the three stages of PV and their associated activities are outlined. This is where we see the most significant

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The FDA’s draft Process Validation guidance activities. Significantly by grouping the recommendations for Product and Process design together in this stage it infers an integrated approach. Within this integrated approach it directly recommends that the team responsible for process design take early consideration of the functionality and limitations of commercial manufacturing equipment: utilising their knowledge about measurement systems in a production setting; contributions to process variability from different raw materials or component lots; and the proposed role of the production operators in providing feedback and continued process verification. This ethos will no doubt be welcomed by many involved in the start up of regulated commercial manufacturing facilities who have dealt with the challenges posed when this early integration of product and process design has not been successful.

the process requirements in all anticipated operating ranges for routine production ★ Challenging the equipment or system functions while under loads comparable to that expected during routine production. ★ Performance of interventions, stoppage and start-up as is expected during routine production.

The guidance requires that these qualification activities are covered either under an individual plan or as part of an overall project plan. In line with ICH Q9, the plan should consider the use of risk management to prioritize certain activities and to identify the appropriate level of effort for both the performance and the documentation of these qualification activities. In conclusion, it confirms the requirement for the qualification activities to be documented in a report with conclusions that specifically address the criteria set out in the plan. It is important to note the expectation that the quality control unit must review and approve both the qualification plan and the report. There is divergence here with the recently published ASTM E2500-073 standard which seeks Quality Unit pre-approval of the acceptance criteria but not the plan but concurs on the Quality Unit post approval of the report.

Stage 2: Process qualification

This stage is undoubtedly going to generate the most comment, and perhaps lead to some confusion due to terminology. The stated goal is that ‘the process design is confirmed as being capable of reproducible commercial manufacture’. The guidance further divides this stage into two elements:

Stage 2-2: Performance Qualification (PQ) The PQ is the second element of the overall process qualification and combines the actual qualified facility, utilities, equipment with the trained personnel, the commercial manufacturing process, the control procedures (SOPs), and (perhaps differently to what was previously understood within the scope of PQ) all raw materials and components necessary to produce commercial batches. The stated goal of the PQ is to ‘confirm the process design and demonstrate that the commercial manufacturing process performs as expected’. Success at this stage is an important milestone in the product lifecycle and needs to be completed before a manufacturer commences commercial distribution of the drug product. This approach to PQ should be based on sound science and the manufacturer’s overall level of product and process understanding. So where to date, PQ was followed by the traditional three PV batches, now no fixed number of new PQ batches are prescribed and manufacturers must provide justification for any rationale used. The guidance provides specific recommendations

Stage 2-1: Design of a facility and qualification of utilities and equipment This section of the guidance opens with a welcome reference to the essential role that proper facility design and commissioning play in the start up of a facility and cites them as prerequisites to the commencement of PQ. Most significantly, the guidance gives a key definition for Qualification: ‘Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in this guidance as qualification’

In summary the guidance states that qualification of utilities and equipment generally includes the following activities:

★ Selecting utilities and equipment based on whether they are appropriate for their specific use. ★ Verifying that the utility system and equipment are built/installed in compliance with the design specifications and operate in accordance with

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The FDA’s draft Process Validation guidance on the format and content of the PQ protocol and the report and elaborates on the opportunities presented for manufacturers utilizing PAT systems.

(cont.)

through the application of product and process knowledge. The welcomed elimination of traditional, prescriptive terminology such as DQ, IQ and OQ offer teams real opportunities to look behind their prepared templates and design and execute programs which are not only valid but valuable to the ongoing operation and continuous improvement. There is only one minor exception relating to an external cross reference to the ICH Q7A API guidance in the introduction, which is likely to add confusion rather than clarity, which hopefully will be dealt with through the public comment phase. Additionally, aligning this PV guidance with the current EMEA legislative requirements for PV needs to be addressed in the commenting period.

Stage 3: Continuous process verification

The goal of the third process validation stage is to ‘continually assure that the process remains in a state of control (the validated state) during commercial manufacture’. This will require robust systems for detecting unplanned departures from the designed process and there is a strong emphasis on statistically trended data which is reviewed in a timely manner by trained personnel. It highlights that maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. Finally, it states a fundamental tenet that following the scientific based approach requires information transparency and accessibility so that organisational units responsible for the process can make informed, science-based decisions that ultimately support the release of a product to commerce.

Nuala Calnan is a Principal Consultant with PM Group, Ireland. She is a member of the ISPE International Board of Directors and was a member of the Author Task Team which produced the recent ASTM E2500-07 International Standard. She is also a member of the team currently updating the ISPE Baseline Guide for C&Q. (Nuala.Calnan@pmg.ie).

In conclusion

It is the opinion of the authors that this guide will be welcomed for many reasons, primarily for the clarity and simplicity of the integrated 3 stage lifecycle process but also for the emphasis on the need for effective and efficient programs which seek to reduce unnecessary duplication in activities

Alice Redmond, PhD is CQ Technical Director with PM Group. She is an active member of ISPE and PDA. She co-chaired and presented at the ISPE GEP ICQ conference in Copenhagen in 2006, and Singapore ISPE July 2008. (Alice.Redmond@pmg.ie).

Industrial Pharmaceutical Microbiology Standards & Controls Editors: Norman Hodges and Geoff Hanlon

“An exceptional and unique publication in this field” Microbiologist – September 2007

21 Chapters 450+ pages £325.00

For details and to order visit the Euromed website: www.euromed.uk.com vol 7 no 4 January 2009

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The FDA's draft Process Validation guidance  

November 2008 saw the draft publication of the FDA’s long anticipated Guidance for Industry on ‘Process Validation: General Principles and P...

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