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

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 IQ and OQ and Calibrations need to be performed prior to use of equipment 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 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 Solids: Tablets & Capsules Liquids – Solution Suspensions Emulsions Lyophilized Ointments / Creams

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

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

Suspensions Milling Mixing Viscosity Resuspendability Agglomeration Caking

Emulsions Homogenation / Emulsification Viscosity Creaming Reemulsify Coalesce Globule Growth

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

Ointments / Creams Active Distribution Particle Size Mixing Emulsification Viscosity

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 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 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 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 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

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.

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 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 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 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 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).

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

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 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 Compendial Analytical Procedures Noncompendial Analytical Procedures and Validation Requirements

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 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

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

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 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) 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 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 Revision and change control procedures Documented evolution of changes Qualified personnel