Pharmaceutical Validation

• Validation is documented evidence which provides a high degree of assurance that a specific process/equipment will consistently produce a product meeting its pre-determined specifications and quality attributes.

Key Aspects of Validation

• Evidence in validation means good science and extensive sampling
• Documented validation means protocols and records are included in the study
• Consistency in validation relates to multiple batches produced by the same process
• Predetermined validation means the knowledge of the API/Drug Product being tested

History of Validation

• 1648: Validation appears in written English
• 1948: The first paper on media fill as a method to validate aseptic filling
• 1971: The Orange guide was published
• 1976: The FDA publishes proposed cGMPs
• 1983: The Orange guide was revised
• 1987: The FDA publishes guidelines on principles of process validation
• 1993: The FDA publishes guidelines for the inspection of the cleaning process
• 2004: 5-Revised schedule M of Drugs & cosmetic act

Reasons to Validate

• Most processes and products cannot be 100% verified or tested
• Validation ensures that systems, materials, methods, and products perform as expected with reliability, reproducibility, and consistency
• Validation ensures quality products, reduces reject rates, and can facilitate troubleshooting of processes at the time of process failure
• High product quality ensures customer satisfaction and minimizes potential for recall
• Understanding Equipment, Systems, and Processes simplifies troubleshooting, process improvement, product transfer, and subsequent related product start-up

Outcomes of Validation

• Cost Reduction: fewer rejects, longer equipment life, reduced in-process and finished product testing
• Regulatory Success: successful inspections, approved products, and the ability to export

Key Definitions

• Installation Qualification(IQ), Operational Qualification (OQ), Performance Qualification (PQ) and Process and Product Validation (PV) are key phases of validation
• Design Qualification and Design of Experiments are used as part of pre-qualification and pre-validation activities

What Needs Qualification

• Each product and the types of controls needed to manufacture it according to specifications needs qualification
• Things to consider are Utilities, Environment and Facilities

Utilities Qualification

• Process Utilities (e.g., Product Contact Utilities) require extensive IQ/OQ testing, unlike non-product contact utilities
• Facility Utilities (e.g., Building or Non-Product Contact) require less extensive IQ/OQ testing

Environment Qualification

• Controlled Environments such as Process Rooms, designed for a specific environment classification need qualification
• Critical operating variables include temperature, relative humidity, airflow, air exchange rate, differential pressure, and filtration.

Environmental Design Considerations

• Pressure differentials can be positive or negative
• Monitor viable microbial particulates via airborne microbial and surface microbial sampling
• Monitor both static and dynamic conditions which is a challenge during validation
• Establish an environmental baseline and trend viable and non-viable particulate monitoring

Design Qualification

• Design Qualification is the documented verification that facilities, systems, or equipment meet user requirements and regulatory expectations
• It focuses on design suitability for operational and performance needs
• Drawing, design, and engineering review must occur
• GMP and process control input must be considered
• Applicable industry standards defined
• Monitoring and control systems must be present
• Cleaning and sanitization aspects must be considered
• There must be appropriate Layouts and finishes
• There must be appropriate Material people flow

Installation Qualification

• Installation Qualification establishes confidence that equipment and ancillary systems are installed according to the design specifications and documentation
• The installation qualification verifies that physical components of the system have been installed according to the design specification
• The IQ is a final major component and system quality audit prior to equipment operation
• The installation of the system will be verified by reviewing the equipment installed
• Check sheets in the protocol as well as forms will be utilized to document the installation of the system.
• The Installation Qualification verifies that system components conform to design specifications
• Engineering documentation is reviewed and compared to the installed system.

Typical Installation Qualification (IQ) Test Functions

• Equipment, Utilities, Instruments, and Drawings List
• Construction Material List
• Calibration, Maintenance and Operating SOPs
• Safety Specifications and Safety Devices
• Hazop Review and Engineering Documentation
• Electrical Connection Verification

Possible Installation Qualification (IQ) Test Functions

• Lubricant List - product contact lubricants must be food grade
• Motor List, critical motor specifications such as manufacturer, model number, serial number, shaft size, amperage, and rotation
• Vacuum Leak Rate Test, verification that pipe joints and valves have installed correctly
• Change Parts or size parts, used to convert equipment to other product and container configurations
• Filter list of filters, confirms that they comply with specifications and Integrity testing

Operational Qualification

• Operational Qualification (OQ) establishes confidence through documented evidence that equipment and supporting systems are capable of consistently operating within intended operating ranges.

Typical Operational Qualification (OQ) Test Functions

• Calibration of qualification test instruments
• Indicators, alarms, interlocks, and safety controls
• SOPs and Training Verification
• Functional testing, PLCs, controllers, software, and equipment operation

Process Validation

• Process Validation establishes confidence through documented evidence that the process, operated under a range of operating conditions, is effective and reproducible
• Manufacturing product or placebo (product without an active) through at worst case conditions is an example

Types of Validation

• Prospective validation applies to new formulas, processes and/or facilities and must be validated before routine pharmaceutical production commences
• Concurrent validation applies to in-process monitoring of critical processing steps and product testing of current production batches
• Retrospective validation applies to achieving validation by documenting all the historical information and using that data to support the position that the process is under control

Revalidation Reasons

• Product Reformulation, major changes/modifications to processing equipment, or the use of new equipment
• Equipment malfunctions or process failures that require batch rework/reprocessing
• In-process test failures, repeated product failures or recurrent stability test results failure
• Unexpected increases in serious adverse experiences

Manufacturing Processes

• Requires process flow charts
• Requires critical variables measured response, blending time, content uniformity, drying temp, and moisture content
• Requires raw material source, name of the material, specifications, source, and analytical reference number
• Requires equipment name and make

Manufacturing Checklist

• Includes weighing, balance number, temperature/ % RH, calibration status, and SOP reference number
• It includes sifting, asset number, sieve number, mixing, asset number, RPM of the blender, and RPM of the agitator and granulator

Sampling Procedure

• The sampling procedure documentation should include the stage, sampling time, sampling position, and acceptance criteria

Documentation

• A validation report, its stage, critical variable, acceptance criteria, results, and conclusions is required
• Batch Manufacturing and Q.C analysis reports of the In-process bulk, finished product and validation sample are required

Experiments vs Validation

• Validation is not an experiment
• Experiments include optimization, process improvement, process capability studies and worst case testing

Critical Process Parameters

• A process step, condition, test requirement, or item that must be controlled within predetermined criteria to ensure that the API/DP meets its specification
• They should extend to those operations critical to the quality of API/DP
• Critical parameters/attributes are normally identified during the development stage or from historical data
• These parameters can be controlled and measured by operators manually or electronically
• Critical parameters and ranges should have been identified in Process Development Reports

Outline Procedure

• Prepare a detailed validation protocol, which is step one in the process
• Manufacture at least 3 consecutive validation batches using a standard, documenting the manufacturing procedure
• Take samples and complete batch records and validation recordings
• Test comprehensively to confirm compliance with specification and all critical quality attributes.
• Then, it is necessary to prepare and sign off the validation report, after which commercial (full scale) product stability can be initiated

Process Validation Documentation

• Formal records are required.
• Process parameters must be recorded and validation trials must be conducted properly.
• Could use a special batch record or data sheet to record checks and samples
• Include all necessary sampling points and acceptance criteria
• Include copies of executed batches

Validation Performance

• The work must followed the protocol, documenting any discrepancies
• Before releasing the product, all discrepancies must be reviewed, justified and approved
• The summary report must address all discrepancies

Cleaning Validation

• Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in equipment
• It lowers the scientifically set maximum allowable carryover level
• Health Based Exposure Limits (HBELs) refer to daily doses of a substance below which no adverse effects are anticipated for a lifetime and are required for cleaning validation of hazardous products
• They are derived from scientific evaluation

Cleaning Validation Terms

• No Observable Adverse Effect Level (NOAEL) must be established for all critical effects identified which defines the highest tested dose at which no adverse effect is observed
• Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) are similar terms

Maximum Allowable Carryover

• MACO is a mathematically calculated quantity of residue from a previous product that can represent potential harm to a patient, considering factors such as toxicity, mode of administration, batch size, and shared equipment surface area.

Risk-Based Approach

• The risk-based approach is based on Health Based Exposure Limits, good knowledge management (ICH Q10), and risk-based principles (ICH Q9)
• The approach includes risk assessments for operations, cross-contamination strategies for patient protection, and managing contamination risks via scientific methodologies in shared facilities

Bracketing for Cleaning Validation

• Groups are typically based on equipment train, cleaning procedure, and/ or dosage form.

Worst-Case Determination

– A crucial step in defining contamination limits, considering factors like batch size, product potency, cleanability, release mechanism, product toxicity, product solubility, and product contact area

Worst-Case Process Conditions

• Campaign length, dirty hold time, and minimum limits for manual cleaning (time for cleaning steps, temperature, and CIP programs) are taken into account

Health-Based Exposure Limits

• The first step in establishing health-based exposure limits is Hazard Identification, using LD50, repeat-dose toxicity, carcinogenicity, mechanism of action, reproductive toxicity, genotoxicity and developmental toxicity
• Second step in establishing health-based exposure limits is is to identifying "Critical Effects," using Clinical & non-clinical studies, Therapeutic effects, and Adverse effects
• Third step in health-based exposure limits is to determine the No Observable Adverse Effect Level (NOAEL), using Step 1 and 2 evaluation, requiring toxicological expertise and is defined as mg/kg/da

Permitted Daily Exposure

• The fourth step in establishing health-based exposure limits is to determine PDE
• PDE is derived from NOAEL, expressed as mg/kg/day and a weight adjustment of 50 kg

Acceptable Daily Intake

• ADE(mg/day) = NOAEL x Weight Adjustment / UFc x MF x PK
• Where UFC is the Composite Uncertainty Factor, MF is the Modifying Factor and PK is the Pharmacokinetic Adjustments

Maximum Allowable Carryover, Simplified

• MACO (mg) = PDE x MBSnext / SF x TDDnext, where:
  • PDE is the Permitted Daily Exposure in Step 4
  • MBSnext is the Min. Batch Size
  • SF is a Safety Factor
  • TDDnext is the Standard Therapeutic Daily Dose (mg/day)

Revalidation is Required When

• A new “worst-case” product is introduced
• There is a change in “product contact” equipment
• There is change in bracketing approach
• Validation should be assessed for impact

Microbiological Risks

• Maintaining appropriate sampling method and handling before testing are important, as are validated test methods with acceptable recovery and identification of objectionable organisms.
• The method chosen represents "worst-case" locations and requires trained personnel