Detailed Analysis of FDA´s New Process Validation Guidance

In November 2008 the FDA published a draft to revise their old Guideline on Process Validation from 1987. The ECA analysed this draft (see GMP News from 26 November 2008) in details and evaluated a detailed survey about the content of this draft (see GMP News from 11 March 2009). The result of this survey was also sent to the FDA as a comment.

Now, on 25 January 2011 the FDA puplished the final version. A summary you can read in the GMP-News from 27 January 2011 What are the differences to the draft? In the following you can read an analysis of the changes (in general minor changes are not mentioned explicitly in any case, conspicuity are printed in italic):

Table of Content

  • New structure concerning changes
  • New subchapter II A Process Validation and Drug Quality,
  • New subchapter II B Approach to Process Validation 
  • New structure of chapter Recommendations in A (General Considerations), B (Stage 1), C (Stage 2), D. (Stage 3)
  • New Glossary
  • References mentioned


  • Emphasis to use ICH Q 8, 9 und 10
  • Explicitly mentioned: term commercial manufacturing (old term was commercial production) with definition explained in a footnote  


B. Approach to Process Validation

  • Slight different definition of process validation and stage 1 and stage 2:

Process Validation: T

he 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.

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.
  • Occurence of multiple stages mentioned
  • Statement:  the approach is to control of the manufacturing process that results in products with the desired quality attributes.
  • Statement: focusing exclusively on qualification efforts ...may not lead to adequate assurance of quality.
  • New clause regarding process improvements: Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify process or product problems or opportunities for process improvements that can be evaluated and implemented through some of the activities described in Stages 1 and 2.
  • New clause regarding process improvements for legacy products: Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3.


  • New sentence: The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements  and do so consistently and reliably.
  • Concretisation regarding CFR requirements for sampling in process control  for validation.
  • Additional minor changes regarding the wording 


A. General Considerations for Process Validation

  • New bullet point regarding the terms attribute(s)  and parameter(s).The magic word behind is "risk based approach". Variations of terminology usage is individual and acceptable but should be communicated to the Agency:  The terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process,operating, and equipment) are not categorized with respect to their criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful. All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk. The Agency recognizes that terminology usage can vary and expects that each manufacturer will communicate the meaning and intent of its terminology and categorization to the Agency.
  • New bullet point regarding single source products and complicated manufacturing processes with the message, that batch homogeneity is the goal of validation: Many products are single-source or involve complicated manufacturing processes. Homogeneity within a batch and consistency between batches are goals of process validation activities. Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health.
  • B. Stage 1 - Process Design

    • Slight change regarding Process design: Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records

    1. Building and Capturing Process Knowledge and Understanding

    • Clarification of viral and impurity clearance studies: Although often performed at small-scale laboratories, most viral inactivation and impurity clearance studies cannot be considered early process design experiments. Viral and impurity clearance studies intended to evaluate and estimate product quality at commercial scale should have a level of quality unit oversight that will ensure that the studies follow sound scientific methods and principles and the conclusions are supported by the data.

    2. Establishing a Strategy for Process Control

    • Two new, very interesting sentences: Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained. FDA expects controls to include both examination of material quality and equipment monitoring.
    • Footnotes on ASTM Guides regarding PAT

    C. Stage 2 - Process Qualification

    • New term Process Performance Qualification (PPQ)

    1. Design of Facility and Qualification of Utilities and Equipment

    • Term qualification mentioned:  Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly.
  • Qualification plan: supplement of the item 4 responsibilities: The plan should identify the following items:
  • 4. The responsibilities of relevant departments and the quality unit

    2. Process Performance Qualification (new title of this subchapter)
    • Generally: term PPQ substitutes old term PQ
    • Ammendment of the PPQ (former PQ) approach: The approach to PPQ should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control.
    • Enhanced sampling and monitoring activities required: The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to, volume of production, process complexity, level of process understanding, and experience with similar products and processes.
  • Process Performance Qualification Protocol: last bullet point contains new term and is supplemented due to risk-based approach and process ability: Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products.
  • New Footnote about FDA Guidance on handling OOS-results regarding deviation
  • D. Stage 3 - Continued Process Verification

    • New term  "undesired process variability" (deletion of the term process drift) and more focus on "CAPA-like" actions: Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control
    • Quality attributes should be appropriately controlled
    • Footnote about some references, e. g. ASTM-Guides regarding Capability Indices, ASTM-Guid regarding Verification
    • Change of the term (process) drift to unintended process variability and undesirable process variation.
    • Supplement of the sentence: We recommend that the manufacturer use quantitative, statistical methods whenever appropriate and feasible.
    • Remark on  211.180(e) for the continued process verification program
    • Changes in the monitoring/sampling chapter: We recommend continued monitoring and sampling of process parameters and quality attributes at the level established during the process qualification stage until sufficient data are available togenerate significant variability estimates. These estimates can provide the basis for establishinglevels and frequency of routine sampling and monitoring for the particular product and process.
  • Change concerning process changes: Depending on how the proposed change might affect product quality, additional process design and process qualification activities could be warranted (with regard to a footnote mentioning 21 CFR 314.70 and 601.12 as an example)
  • Concretisation regarding re-qualification:  equipment and facility qualification data should be assessed periodically...

    • Generally: term PPQ substitutes old term PQ
    • Focus on high degree of process assurance for distribution: In most cases, the PPQ study needs to be completed successfully and a high degree of assurance in the process achieved before commercial distribution of a product.
    • Supplement regarding concurrent release: In special situations, the PPQ protocol can be designed to release a PPQ batch for distribution before complete execution of the protocol steps and activities, i.e., concurrent release.
    • Clarification of products which might be concurrent released: Concurrent release might be appropriate for processes used infrequently for various reasons, such as to manufacture drugs for which there is limited demand (e.g., orphan drugs, minor use and minor species veterinary drugs) or which have short half lives (e.g., radiopharmaceuticals, including positron emission tomography drugs).
    • New subchapter explaining the necessary of  completing PPQ: Conclusions about a commercial manufacturing process can only be made after the PPQ protocol is fully executed and the data are fully evaluated. If Stage 2 qualification is not successful (i.e., does not demonstrate that the process as designed is capable of reproducible performance at commercial scale), then additional design studies and qualification may be necessary. The new product and process understanding obtained from the unsuccessful qualification study(ies) can have negative implications if any lot was already distributed. Full execution of Stages 1 and 2 of process validation is intended to preclude or minimize that outcome.
    • New subchapter explaining circumstances and rationale for concurrent release: Circumstances and rationale for concurrent release should be fully described in the PPQ protocol. Even when process performance assessment based on the PPQ protocol is still outstanding, any lot released concurrently must comply with all CGMPs, regulatory approval requirements, and PPQ protocol lot release criteria. Lot release under a PPQ protocol is based upon meeting confidence levels appropriate for each quality attribute of the drug.
    • Supplements concerning failures in PPQ and concerning stability programme: Concurrently released lots must also be assessed in light of any negative PPQ study finding or conclusions and appropriate corrective action must be taken (§§ 211.100(a), 211.180(e), and 211.192). We recommend that each batch in a concurrent release program be evaluated for inclusion in the stability program.


    • New supplement regarding the validation life cycle: The degree and type of documentation required by CGMP vary during the validation lifecycle.

    • New sentence: Validated analytical methods are not necessarily required during product- and process-development activities or when used in characterization studies.
    • Clarification of the use of new analytical methods and regarding clinical studies: New analytical technology and modifications to existing technology are continually being developed and can be used to characterize the process or the product. Use of these methods is particularly appropriate when they reduce risk by providing greater understanding or control of product quality. However, analytical methods supporting commercial batch release must follow CGMPs in parts 210 and 211. Clinical supply production should follow the CGMPs appropriate for the praticular phase of the clinical studies.


    • Chapter completely new


    • Updating of FDA references and supplement of ASTM Guides.


    The final version does not include neither the term prospective, nor the terms concurrent (only concurrent release) or retrospective validation. Process validation is a life cycle approach with 3 stages. A number of validation batches is not mentioned. Based on a risk based approach statistics should give a scientific sound rationale, when a process is valid. Old processes should be evaluated towards development experiences, qualification work and of course routine production experience. So (re)validation of old processes start with stage 3.  IQ and OQ are not mentioned, but the term qualification is still mentioned. Terms like critical quality attribute and critical process parameter are not included. These terms are covered automatically in validation, if you use ICH Q8, Q9 and Q10. You don´t find the expression worst case. During Stage 1 and 2 manufacturers gain a lot of data. With these data they can demonstrate that the process is capable (including conditions that pose a high risk of process failure). A lot of ASTM-Guides are referenced as state of the art.

    This new FDA Guidance is actually the most modern GMP Guidance on Process Validation and will probably have a signal effect for other authorities.

    For further information please also see the final guidance.

    During ECA´s 4th biannnual GMP Conference a session will highlight FDA´s new Process Validation Guidance but also the movement regarding Validation in Europe. To find out more plese visit the conference website at

    Sven Pommeranz
    Concept Heidelberg (a service provider entrusted by the ECA Foundation)

    PS: In the members area you will find a comparison between the draft and the final guidance.

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