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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

Process Analytical Technologies

February 2002

FDA Subcommittee Meeting

Process and Method

Validation

Leon Lachman, Ph.D.

President

Lachman Consultant Services, Inc.

validation
Validation

“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.”

qualification validation of pharmaceutical processes
Qualification / Validation of Pharmaceutical Processes

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

european agency guidance for process validation
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.
european agency guidance for process validation5
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.
representative dosage forms
Representative Dosage Forms
  • Solids: Tablets & Capsules
  • Liquids – Solution
    • Suspensions
    • Emulsions
  • Lyophilized
  • Ointments / Creams
solids tablets capsules
Size Reduction

Blending

Granulating

Compressing

Encapsulation

Coating

Solids: Tablets & Capsules
powder blending operation
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)
liquids solution
Solution Studies of Ingredients

Fill Uniformity

Filter Compatibility

Product Tubing Interaction

Flush Volumes

Cleaning / Sanitization

Inert Gas Effectiveness

Bioburden

Pyroburden

Liquids - Solution
suspensions
Suspensions
  • Milling
  • Mixing
  • Viscosity
  • Resuspendability
  • Agglomeration
  • Caking
emulsions
Emulsions
  • Homogenation / Emulsification
  • Viscosity
  • Creaming
  • Reemulsify
  • Coalesce
  • Globule Growth
lyophilized
Freezing

Temperature

Rate

Drying

Temperature

Vacuum

Cake Appearance

Dissolution

Melt Back

Lyophilized
ointments creams
Ointments / Creams
  • Active Distribution
  • Particle Size
  • Mixing
  • Emulsification
  • Viscosity
method validation
Method Validation

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.

method validation15
Method Validation

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)
ich topic q2b validation of analytical procedures
ICH Topic Q2BValidation 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.
considerations prior to method validation
Considerations Prior to Method Validation
  • 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
examples of methods that require validation documentation
Examples of Methods That Require Validation Documentation
  • 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.
method characteristics to be considered for validation
Specificity (Selectivity)

Linearity

Range

Accuracy

Precision

Repeatability

Intermediate Precision

Reproducibility (Ruggedness)

Detection Limit

Quantitation Limit

Robustness

System Suitability Testing

Method Characteristics to Be Considered for Validation
specificity
Specificity
  • 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.
specificity21
Specificity
  • 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.
linearity
Linearity
  • 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.
range
Range
  • 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.
accuracy
Accuracy
  • 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.
precision
Precision
  • 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).
detection limit
Detection Limit
  • 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.
quantitation limit
Quantitation Limit
  • 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.
impurities quantitation
Impurities (Quantitation)
  • Accuracy should be assessed on samples (substance / product) spiked with known amounts of impurities.
robustness
Robustness
  • 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.
system suitability testing
System Suitability Testing
  • 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.
regulatory approaches
Regulatory Approaches
  • Compendial Analytical Procedures
  • Noncompendial Analytical Procedures and Validation Requirements
compendial analytical procedures
Compendial Analytical Procedures

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
compendial analytical procedures33
Compendial Analytical Procedures
  • 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.
appropriate automation can
Reduce variability associated with human interaction

Increase knowledge of process

Improve monitoring, control and decisions

Improve process and product consistency

Improve documentation & reporting capabilities

Reduce costs

Appropriate Automation Can….
advantages process validation
Advantages…Process Validation
  • 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
consequences of inadequate automation
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:

downtime

rejection of in-process and finished product

product recalls

eroded goodwill

Consequences of Inadequate Automation
calibration and maintenance
Calibration and Maintenance
  • 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
compliance issues automated equipment
Compliance Issues…automated equipment
  • 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
compliance issues automated equipment continued
Compliance Issues…automated equipment(continued)
  • Operating Environment
    • defined; controlled; documented
  • In-Process Control Data…use and retention
  • SOPs and Training
  • Data Integrity
  • Legacy Systems
closed system controls
Validation

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
closed system controls continued
Written policies & procedures

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
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