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1 USFDA- Guidance for Industry Process Validation: General Principles and Practices 2011 By: Akhilesh Kumar Dwivedi Dr. Reddy’s Labs. F.T.O-III Date: 21 Feb. 2011

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Revised USFDA process validation 2011


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USFDA-Guidance for Industry

Process Validation: General Principles and Practices


By: Akhilesh Kumar DwivediDr. Reddy’s Labs. F.T.O-III

Date: 21 Feb. 2011

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The new Process Validation Guideline by FDA, On a total of 20 pages and subdivided into 7 chapters, the FDA now describes their current thinking with regard to process validation. The chapters are subdivided into:






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• The introduction points out expressly that process validation is connected to a product life cycle. Thus, process validation includes development towards routine production and routine production itself. Furthermore, the guidance document intends to promote modern manufacturing principles, process improvement, innovations and sound science. It also refers to ICH Q8, 9 and 10 in connection with the life cycle concept.


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This guidance covers the following categories of drugs:

• Human drugs.

• Veterinary drugs.

• Biological and biotechnology products.

• Finished products and active pharmaceutical ingredients (APIs or drug substances).

• The drug constituent of a combination (drug and medical device) product.


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This guidance does not cover the following types of products:

• Type A medicated articles and medicated feed.

• Medical devices.

• Dietary supplements.

• Human tissues intended for transplantation regulated under section 361 of the Public Health Service Act.


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II. BACKGROUND• The history briefly deals with the FDA Guideline

on Process Validation of 1987 . The current guidance document is based on experience values gathered since 1987 and also on the FDA Initiative cGMPs for the 21st century - a risk-based approach. Here, the text contains another reference to modern manufacturing techniques and to "risk management" and "quality management tools" and "concepts".


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Process Validation Definition

1987 Definition

“Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined

specifications and quality characteristics”

2011 Definition

“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”


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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 of the manufacturing process that results in products with the desired quality attributes. Manufacturers should: •Understand the sources of variation. •Detect the presence and degree of variation. •Understand the impact of variation on the process and ultimately on product attributes. •Control the variation in a manner commensurate with the risk it represents to the process and product.

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ICH Q8/Q8(R) - Pharmaceutical Development

PAT Guidance

ICH Q9 – Quality Risk Management

ICH Q10 – Pharmaceutical Quality Systems


Process Design

Scale-up &Transfer

Commercial Manufacture Product

Focus on alignment with ‘product lifecycle’

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Process Validation = Lab Studies + Development History + Commercial Scale-up Manufacturing @ Target Values + On-going Monitoring

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• In this chapter, the FDA refers to paragraphs in 21 Code of Federal Regulation 210/211 that also have to be applied with regard to validation (and qualification of equipment): 211.100(a), 211.110(a)(b), 211.160(b)(3), 211.165 (a)(c)(d), 211.180(e), 211.42, 211.63, 211,68.


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IV. RECOMMENDATIONS• A. General Considerations for Process Validation.

• B. Stage 1 ― Process Design.

• 1. Building and Capturing Process Knowledge and Understanding.

• 2. Establishing a Strategy for Process Control.

• C. Stage 2 ― Process Qualification.

• 1. Design of a Facility and Qualification of Utilities and Equipment.

• 2. Process Performance Qualification.

3. PPQ Protocol.

4. PPQ Protocol Execution and Report.

• D. Stage 3 ― Continued Process Verification.


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• Stage 1 – Process Design: The commercial manufacturing 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 evaluated to determine if the process is 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.

The new guidance has been aligned with this concept, giving the following three-stage approach to process validation:

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1.Process Design

IntentTo define the commercial

process on knowledge gained

through development and

scale up activities. The outcome is the design of a process suitable for routine manufacture that will

consistently deliver product

that meets its critical quality


Typical Activities

A combination of product and process design (Quality by Design).

Product development activities. Experiments to determine process

parameters, variability and necessary controls.

Risk assessments. Other activities required to define

the commercial process. Design of Experiment testing.


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2.Process Qualification

To confirm the process

design as capable of

reproducible commercial


Facility design. Equipment & utilities

qualification. Performance qualification

(PQ). Strong emphasis on the use

of statistical analysis of process data to understand process consistency and performance.


Intent Typical Activities

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Process Qualification

• 1. Design of a Facility and Qualification of Utilities and Equipment.

• 2. Process Performance Qualification .

• 3. PPQ Protocol .

• 4. PPQ Protocol Execution and Report.


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3.Continued Process Verification

To provide ongoing

assurance that the process

remains in a state of control

during routine production

through quality procedures

and continuous improvement


Proceduralised data collection from every batch.

Data trending and statistical analysis.

Product review. Equipment and facility

maintenance. Calibration. Management review and

production staff feedback. Improvement initiatives through,

process experience.


Intent Typical Activities

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• In rare cases concurrent release is also possible, i.e. a release of the product before the entire PQ protocol has been completed. Possible cases include orphan drugs (limited demand for the product) and radiopharmaceuticals. Yet, the guidance recommends the manufacturer to contact the FDA before implementing concurrent release. Batches marketed within the framework of concurrent release should be traced back very closely in order to be able to take immediate action in case of complaints (root cause). Furthermore, each batch manufactured under concurrent release should immediately be included in a stability programme.


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• Documentation is considered very important during each stage of the process validation life cycle. On the basis of the process design (stage 1), the guidance recommends to draw up process flow charts for the full-scale process. Apart from that, the text refers to 21 CFR 211.22 and 211.100.


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• While analytical methods do not have to be validated in the (early) development stages, but have to be scientifically sound, analytical methods of the clinical phases 2 and 3 are subject to cGMP.


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The Golden Three Batches:• Although not expressly stated in the old guidance, manufacture of

three batches for process validation has become industry standard. For some time now, the FDA has been trying to steer manufacturers away from this thinking, and to be more critical in determining how many batches are required for effective process validation.

• The new guidance makes it clear that it is the manufacturer’s responsibility to provide assurance that the process is adequately qualified. The use of statistical methods to provide objective evidence of this is strongly recommended.

• In practice, this may mean that 3 batches is sufficient to provide the necessary data, or it may be that more are required (it is unlikely to be less). The manufacturer needs to assess, justify and clearly state those requirements during the preparation of the PQ protocol.


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Revision of worst-case concept:

• The concept of worst-case conditions for process validation was a key theme of the 1987 guidance. The 1987 guidance defines worst-case as “A set of conditions encompassing upper and lower limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions.”


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• The 2008 guidance has not only removed the concept of worst-case conditions, it has redefined the expectation as follows:

“The commercial manufacturing process and routine procedures must be followed. The PQ lots should be manufactured under normal

conditions by personnel expected to routinely perform each step of each unit operation in the process.”

• The new guidance shifts the responsibility for addressing processing variability to the Process Design stage of validation activities. It is intended that product development studies and risk analysis should address process variability and quantify the effects on the product where possible.

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Revision of the revalidation concept:

• The 2008 guidance has revised this concept with the introduction of Continued Process Verification. This involves the on-going assessment of process data (in-process, finished product, equipment parameters, etc) against variability limits established during the first two stages of process validation.


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Matrix approach:

• Matrix approaches to process validation, where multiple similar products, presentations or equipment are grouped together within the one validation exercise to reduce the overall testing requirements, was expressly discouraged in the 1987 guidance. Conversely, the 2008 guidance provides specific acceptance of the practice, stating “Previous credible experience with sufficiently similar products and processes can also be considered”.


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Concurrent & Retrospective validation:

• The concept of concurrent validation was not included in the 1987 guidance. The new guidance provides information on the precise circumstances under which concurrent release of validation batches is acceptable. These include infrequent product manufacture, necessarily low volume manufacture (e.g. radiopharmaceuticals) and manufacture of medically necessary products in short supply. Additional expectations for customer feedback and stability are stated for concurrent validation batches

• Retrospective validation is not mentioned in the guidance and is no longer considered acceptable.


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Other Changes:

Also of note is the acknowledgement of some concepts which have gained wide acceptance in industry including:•Integrated team approach – the guidance strongly recommends input in the validation process from a wide range of disciplines, as well as the full support of senior management.•Process Analytical Technologies (PAT) – the guidance introduces PAT concepts and gives guidance on the role it can play in process validation


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• The new guidance relies on a 3-stage life cycle model. The new catchword is "process understanding". New definitions for process validation and performance qualification show the strong connection to "scientific sound". Strong emphasis is also placed on the use of statistical methods. "Modern" methods from the world of six sigma, like DoE, process capability indexes (Cpk) and statistical process control are mentioned directly or indirectly.


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Any Question...

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Thank You..