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

2. 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.”

3. Qualification / Validation of Pharmaceutical Processes
IQ and OQ and Calibrations need to be performed prior to use of equipment for process validation.

4. 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.

5. 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.

6. Representative Dosage Forms
Solids: Tablets & Capsules
Liquids – Solution
Suspensions
Emulsions
Lyophilized
Ointments / Creams

7. Solids: Tablets & Capsules
Size Reduction
Blending
Granulating
Compressing
Encapsulation
Coating

8. 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)

9. Liquids - Solution Solution Studies of Ingredients Fill Uniformity
Filter Compatibility
Product Tubing Interaction
Flush Volumes
Cleaning / Sanitization
Inert Gas Effectiveness
Bioburden
Pyroburden

10. Suspensions Milling Mixing Viscosity Resuspendability Agglomeration
Caking

11. Emulsions Homogenation / Emulsification Viscosity Creaming Reemulsify
Coalesce
Globule Growth

12. Lyophilized Freezing Drying Cake Appearance Dissolution Melt Back
Temperature
Rate
Drying
Vacuum
Cake Appearance
Dissolution
Melt Back

13. Ointments / Creams Active Distribution Particle Size Mixing
Emulsification
Viscosity

14. 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.

15. 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)

16. ICH Topic Q2B Validation 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.

17. 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

18. 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.

19. 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

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

26. 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.

27. 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.

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

29. 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.

30. 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.

31. Regulatory Approaches
Compendial Analytical Procedures
Noncompendial Analytical Procedures and Validation Requirements

32. 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

33. 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.

34. 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

35. 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

36. 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

37. 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

38. 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

39. Compliance Issues…automated equipment (continued)
Operating Environment
defined; controlled; documented
In-Process Control Data…use and retention
SOPs and Training
Data Integrity
Legacy Systems

40. Closed System Controls
Validation
Electronic and Human readable formats
Protection to ensure accurate and ready retrieval
Authorized access only
Audit trails
Device checks to determine validity of input
Operational system checks, as appropriate

41. Closed System Controls (continued)
Written policies & procedures
Controls over system documentation
Operational system checks, as appropriate
Controls over access to system operation and maintenance
Revision and change control procedures
Documented evolution of changes
Qualified personnel