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Process Analytical Technologies. February 2002 FDA Subcommittee Meeting. Process and Method Validation. Leon Lachman, Ph.D. President Lachman Consultant Services, Inc. Validation.

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Process analytical technologies l.jpg

Process Analytical Technologies

February 2002

FDA Subcommittee Meeting

Process and Method


Leon Lachman, Ph.D.


Lachman Consultant Services, Inc.

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“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 attributes.”

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Qualification / Validation of Pharmaceutical Processes

IQ and OQ and Calibrations need to be performed prior to use of equipment for process validation.

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European Agency Guidance for Process Validation

  • Validation is the act of demonstrating and documenting that a procedure operates effectively.

  • Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.

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European Agency Guidance for Process Validation

  • Change Control: Clearly defined procedures are needed to control changes proposed in production processes. Such procedures should tightly control planned changes, ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specification and ensure that all aspects are thoroughly documented and approved.

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Representative Dosage Forms

  • Solids: Tablets & Capsules

  • Liquids – Solution

    • Suspensions

    • Emulsions

  • Lyophilized

  • Ointments / Creams

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Size Reduction






Solids: Tablets & Capsules

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Powder Blending Operation

  • Equipment: Blender geometry; use of intensifier bars; operating principle; size; recommended powder capacity for efficient blending

  • Blend: Order of addition of ingredients; volume

  • Parameters: RPMs; time

  • Homogeneity: Blender; post-discharge; post-storage; sampling (number; location; size)

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Solution Studies of Ingredients

Fill Uniformity

Filter Compatibility

Product Tubing Interaction

Flush Volumes

Cleaning / Sanitization

Inert Gas Effectiveness



Liquids - Solution

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Suspensions Ingredients

  • Milling

  • Mixing

  • Viscosity

  • Resuspendability

  • Agglomeration

  • Caking

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Emulsions Ingredients

  • Homogenation / Emulsification

  • Viscosity

  • Creaming

  • Reemulsify

  • Coalesce

  • Globule Growth

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Freezing Ingredients






Cake Appearance


Melt Back


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Ointments / Creams Ingredients

  • Active Distribution

  • Particle Size

  • Mixing

  • Emulsification

  • Viscosity

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Method Validation Ingredients

Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products.

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Method Validation Ingredients

Published Guidances

  • ICH-Q2A “Text on Validation of Analytical Procedure:(1994)

  • ICH-Q2B “Validation on Analytical Procedures: Methodology: (1995)

  • CDER “Reviewer Guidance: Validation of Chromatographic Method” (1994)

  • CDER “Submitting Samples and Analytical Data for Method Validations” (1987)

  • CDER Draft “Analytical Procedures and Method Validation” (2000)

  • CDER “Bioanalytical Method Validation for Human Studies” (1999)

  • USP<1225> “Validation of Compendial Methods” (current revision)

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ICH Topic Q2B IngredientsValidation of Analytical Procedures

  • The main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose.

  • In practice, it is usually possible to design the experimental work so that appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision.

  • Well-characterized reference materials, with documented purity, should be used throughout the validation study.

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Considerations Prior to Method Validation Ingredients

  • Suitability of Instrument

    • Status of Qualification and Calibration

  • Suitability of Materials

    • Status of Reference Standards, Reagents, Placebo Lots

  • Suitability of Analyst

    • Status of Training and Qualification Records

  • Suitability of Documentation

    • Written analytical procedure and proper approved protocol with pre-established acceptance criteria

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Examples of Methods That Require Validation Documentation Ingredients

  • Chromatographic Methods – HPLC, GC, TLC, GC/MS, etc.

    • Pharmaceutical Analysis – In support of CMC.

    • Bioanalytical Analysis – In support of PK/PD/Clinical Studies.

  • Spectrophotometric Methods – UV-VIS, IR, NIR, AA, NMR, XRD, MS, etc.

  • Capillary Electrophoresis Methods – Zone, Isoelectric Focusing, Isotachophoresis, etc.

  • Particle Sizer Analysis Methods – Laser, Microscopic, Photozone, Sieving, SEC, etc.

  • Dissolution Methods – Method of Analysis – HPLC, UV, Automated, etc.

  • Titration Methods.

  • Automated Analytical Methods – Robots, Automated Analysis.

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Specificity (Selectivity) Ingredients






Intermediate Precision

Reproducibility (Ruggedness)

Detection Limit

Quantitation Limit


System Suitability Testing

Method Characteristics to Be Considered for Validation

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Specificity Ingredients

  • Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.

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Specificity Ingredients

  • It is not always possible to demonstrate that an analytical procedure is specific for a particular analyte (complete discrimination). In this case a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination.

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Linearity Ingredients

  • The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.

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Range Ingredients

  • The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

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Accuracy Ingredients

  • The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.

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Precision Ingredients

  • Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.

  • Intermediate Precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

  • Reproducibilityexpresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

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Detection Limit Ingredients

  • The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

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Quantitation Limit Ingredients

  • The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

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Impurities (Quantitation) Ingredients

  • Accuracy should be assessed on samples (substance / product) spiked with known amounts of impurities.

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Robustness Ingredients

  • The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

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System Suitability Testing Ingredients

  • System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated.

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Regulatory Approaches Ingredients

  • Compendial Analytical Procedures

  • Noncompendial Analytical Procedures and Validation Requirements

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Compendial Analytical Procedures Ingredients

The Analytical procedures in the USP 25/NF 20 are legally recognized under section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory analytical procedures for the compendial items. The suitability of these procedures must be verified under actual conditions of use. When using USP 25/NF 20 analytical procedures, the guidance recommends that information be provided for the following characteristics:

  • Specificity of the procedure

  • Stability of the sample solution

  • Intermediate precision

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Compendial Analytical Procedures Ingredients

  • Compendial analytical procedures may not be stability indicating, and this concern must be addressed when developing a drug product specification because formulation-based interference may not be considered in the monograph specifications.

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Reduce variability associated with human interaction Ingredients

Increase knowledge of process

Improve monitoring, control and decisions

Improve process and product consistency

Improve documentation & reporting capabilities

Reduce costs

Appropriate Automation Can….

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Advantages…Process Validation Ingredients

  • Expanded real time monitoring and adjustment of process

  • Enhanced ability to statistically evaluate process performance and product variables

    e.g., individuals; mean; range; control limits

  • Enhanced data and evaluation capabilities and increased confidence about process reproducibility and product quality

  • Improved ability to set target parameters and control limits for routine production, correlating with validation results

  • Enhanced reporting capability

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Acquired data may not be complete, accurate and/or representative

Improper evaluation

Process assurance and adjustments based on inadequate information

Process deviations

Product quality problems

Avoidable costs:


rejection of in-process and finished product

product recalls

eroded goodwill

Consequences of Inadequate Automation

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Calibration and Maintenance representative

  • Sensors must be calibrated

    • e.g., time; temperature; pressure; wattage; humidity; weight; force; dimensions

  • Controllers must be qualified, calibrated and maintained at appropriate intervals

  • Environmental requirements for the computerized system must be defined, maintained and documented

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Compliance Issues…automated equipment representative

  • System for reporting and evaluating deviations

    • hardware

    • software

    • security

    • life cycle management

  • Equipment Maintenance

  • Calibration

  • Target and Control Limits

    • versus validated parameters

    • versus historical process performance

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Compliance Issues…automated equipment representative(continued)

  • Operating Environment

    • defined; controlled; documented

  • In-Process Control Data…use and retention

  • SOPs and Training

  • Data Integrity

  • Legacy Systems

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Validation representative

Electronic and Human readable formats

Protection to ensure accurate and ready retrieval

Authorized access only

Closed System Controls

  • Audit trails

  • Device checks to determine validity of input

  • Operational system checks, as appropriate

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Written policies & procedures representative

Controls over system documentation

Operational system checks, as appropriate

Controls over access to system operation and maintenance

Closed System Controls(continued)

  • Revision and change control procedures

  • Documented evolution of changes

  • Qualified personnel