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.
2

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.
4

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. 5

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

10

Emulsions

Homogenation / Emulsification Viscosity Creaming Reemulsify Coalesce Globule Growth

11

Lyophilized

Freezing
Temperature Rate

Drying
Temperature Vacuum

Cake Appearance Dissolution Melt Back

12

Ointments / Creams

Active Distribution Particle Size Mixing Emulsification Viscosity

13

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.
14

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)
15

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.
16

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

17

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. 18

Method Characteristics to Be Considered for Validation

Specificity (Selectivity) Linearity Range Accuracy Precision

Repeatability Intermediate Precision Reproducibility

Detection Limit Quantitation Limit Robustness System Suitability Testing

(Ruggedness)
19

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.

20

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.

21

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.
22

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.
23

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.
24

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 withinlaboratories variations: different days, different analysts, different equipment, etc. Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).
25

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.
26

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.
27

Impurities (Quantitation)

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

28

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.
29

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.
30

Regulatory Approaches

Compendial Analytical Procedures Noncompendial Analytical Procedures and Validation Requirements

31

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
32

Compendial Analytical Procedures

Compendial analytical procedures may not be stability indicating, and this concern must be addressed when developing a drug product specification because formulationbased interference may not be considered in the monograph specifications.
33

Appropriate Automation Can.

Reduce variability Improve process and associated with human product consistency interaction Improve documentation Increase knowledge of & reporting capabilities process Reduce costs Improve monitoring, control and decisions

34

AdvantagesProcess 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
35

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

36

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
37

Compliance Issuesautomated 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
38

Compliance Issuesautomated equipment

(continued)

Operating Environment
defined; controlled; documented

In-Process Control Datause and retention SOPs and Training Data Integrity Legacy Systems
39

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

40

Closed System Controls

(continued)

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