Process Validation Critical Parameters

Process Validation Critical Parameters

Process Validation(FDA Definition)

Establishing Documented Evidence, Which provides a high degree of assurance that a specific process will  consistently produce a product meeting its predetermined specifications and quality attributes.”

Steps in Validating a Process:

  • Develop validation protocol
  • Conduct installation qualification
  • Conduct operational qualification
  • Conduct performance qualification
  • Analyze results and reach conclusions
  • Monitor and control process
  • Purpose: to ensure process remains within established parameters under anticipated conditions
  • Investigate deviations from established parameters
  • Take corrective action
  • Consider whether revalidation is necessary
  • Changes in process or product

Evaluate changes in process, product, procedures, equipment, personnel, environment, etc. to determine effect of change.

Validation Responsibilities

  • Colleagues to administer program – e.g. Technical Services or Site Validation Committee (SVC)
  • Develop site master validation plan.
  • Prepare/execute/approve validation studies.
  • Manufacturing Operations prepares the batches as though they are Routine production batches.
  • QA ensures compliance and that documentation and procedures are in place. Approves protocols and reports.
  • QC Laboratories – performs testing or contracts validation testing. Reviews protocols and reports as needed.
  • SVC – Technology Group (lead),Manufacturing Operations, QA/QC, Engineering,
  • Computer Systems

    A 5 -

Validation Protocol:

Definition: A document stating how validation will be conducted, including test parameters, product characteristics, manufacturing equipment, and decision points on what constitutes acceptable test results.
Contents of validation Protocol:

  • General information
  • Objective
  • Background/Pre-validation Activities, Summary of development and tech transfer (from R&D or another Site) activities to justify in-process testing and controls; any Previous validations.
  • List of equipment and their qualification status
  • Facilities qualification
  • Process flow charts
  • Manufacturing procedure narrative
  • List of critical processing parameters and critical excipients
  • Sampling, tests and specifications
  • Acceptance criteria

Validation- Related Issues

  • Approach to validation
  • SOPs
  • Calibration
  • Environmental monitoring
  • Preventive maintenance
  • Training
  • Raw material sampling and qualification programs
  • Change control
  • Facilities/systems
  • Manufacturing/packaging methods
  • Formulations
  • Raw materials & Suppliers

GMP requirements for Process Design

  • Design of Facility
  • Design of Equipment
  • Design of Production and Control Procedures
  • Design of Laboratory Controls
  • Propose process steps (unit operations) and process variables (operating parameters) that need to be studied.
  • Identify sources of variability each unit operation is likely to encounter.
  • Consider possible range of variability for each input into the operation.
  • Evaluate process steps and variables for potential criticality.
  • Select process steps and variables for test in representative models.
  • Development studies to identify critical operation parameters and operating ranges
  • Designed experiments
  • Lab scale, pilot scale and/or full scale experimental batches to gain process understanding
  • Establish mechanisms to limit or control variability based on experimental data
  • Aim for a “robust process”, i.e., one that can tolerate input variability and still produce consistent acceptable output.


  • Transfer developmental knowledge to Production, i.e., technology transfer.
  • Batch record and operating SOPs in place, equipment and facilities equivalency established.
  • Raw materials approved.
  • Measurement systems qualified (QC lab as well as production floor test instrumentation).
  • Personnel training completed.
  • Environment controlled as necessary.
  • Execution of Conformance Batches with appropriate sampling points and sampling level.
  • First evidence that process can function at commercial scale by Production personnel.
  • Demonstrates reproducibility.
  • Reasonable measure of protection to consumer.
  • Full sample and data analysis
  • Data may confirm process as-is, point to major process design change(s) or suggest process improvement(s).
  • Implement changes via approved change control procedures.
  • Assess need for additional conformance batch(es) or limited testing.
  • Amount/degree of additional work commensurate with the significance of the change and its impact on product quality

Routine Commercial Manufacturing

  • Monitor critical operating and performance parameters
  • Utilize appropriate tools, e.g., Statistical Process Control
  • Monitor product characteristics (e.g., stability, product specifications)
  • Monitor state of personnel training and material, facility/equipment and SOP changes
  • Investigate OOS for root cause and implement corrective action.


  • Analyze Monitoring Data
  • Trend data: e.g., Real time, Monthly,
  • Quarterly review
  • -Evaluate need to increase level of monitoring/sampling, or decreased monitoring based on accumulated data
  • Periodic evaluation (at least annually) per 21
    CFR 211.180(e)
  • To determine the need for changes in drug product specifications or manufacturing and control procedures
  • Study OOS and OOT (out of trend) data in the aggregate.
  • Assess impact of process and product changes made over time.
  • Feed back into design stage for significant process shifts or changes

When changes or process deviations occur, the process must be reviewed and evaluated, and revalidation must be performed where appropriate. Review, evaluation, and revalidation activities must be documented.
Revalidation may be divided into two broad categories:

  • Revalidation after any change having a bearing on product quality.
  • Periodic revalidation carried out at scheduled intervals.
  • Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes,
    equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.).
    Some typical changes which require revalidation include the following:
  • Changes in the starting material(s).Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product.
  • Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability.
  • Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality.
  • Changes in equipment, including measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process.
  • Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process.
  • Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made.

The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during in-process and finished product testing after the latest validation, aimed at verifying that the
process is under control. During the review of such historical data, any trend in the data collected should be evaluated.

Determining the level of lubricants to use and the manner in which they are incorporated into a batch is critical. If concentrations are too low, or distribution and mixing times are inadequate, problems can arise.

Some examples are as follows:

  • Punch filming
  • Picking
  • Sticking
  • Capping
  • Binding in the die cavity

If concentrations are too high, or distribution and mixing times are too great, potential problems include:

  • Decrease in tablet hardness
  • Inability to compress into tablets
  • Increase in tablet disintegration times (DTs)
  • Decrease in rate of dissolution

Compression Parameter to be Control During Validation

A) Description
B) Weight variation (group and individual)
C) Hardness
D) Thickness
E) Friability
F) Disintegration time
G) Dissolution time
H) Content uniformity and
I) Impurities

The coating step involves the covering of tablet surface with a polymer film. The pan RPM, Inlet and Exhaust temperatures, Spray rate, gun distance and air pressure are critical process variables. These parameters affect the coating and final appearance of the tablets.

a) Pan RPM: If the RPM of coating pan is not within the specified limit then uneven distribution of the coating solution on tablet take place.
b) Inlet/Exhaust temperature: If the temperature of coating pan is not within the specified limit then the drying will be insufficient which results twining and sticking of tablets or rough surface and cracking of the film.

c) Spray rate: If the spray rate is not proper then the coating will not be uniform.

d) Gun to bed distance: If gun to bed distance is not adequate, it results in rough surface or over wetting during coating.

e) Air pressure: If the compressed air pressure (Main and Atomization) is not adequate, it peeling or rough surface of tablets.

After completion of coating check for Description, weight variation and moisture content, appearance and weight gain during coating.


Formulation of Suspensions

About Pharmaceutical Guidanace

Ms. Abha Maurya is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 18 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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