Process Validation Current Thinking, Case Studies, and

Lessons Learned

Steven B. Hertz, P.E., M.B.A. Consumer Safety Officer, FDA/CDER/OC/OMPQ

IVT Validation Week, March 27th 2014

Overview

What is PV in ‘14? “State of Control”

Post-Approval Considerations Case Studies

Summary

2010 “Indifference”,

“Comatose”, “Down”, “Sad”, “Help, Help”…

2014 “Smile”, “Just Breathe”,

“Alive”, “Unthought Known”, “It’s Okay”!!!

What is PV? Process Validation as a legal requirement

• Enforceable for finished drug products (21CFR211)

• 100(a) – “written procedures… designed to assure…”

• 110(a) – “procedures… monitor the output & validate the performance”

• Additional PV requirements (for another time…)

• APIs (Q7A), QSR (820.75), HCT/Ps (1271.230)

What is PV?

• Guidance published January 2011

• Authored by CDER, CBER, CVM; input from ORA

• First revision to the original PV guidance published in May 1987

What is PV?

In the revised guidance, process validation is defined as...

“The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.”

What is PV?

PV 1987 vs PV 2011

• 1987 – Processes can be “successfully validated”, and eventually “revalidated” after changes to product and/or process

• 2011 - PV involves a series of activities taking place over the lifecycle of the product and process

What is PV?

When is a process “validated”?

• The PV stages are important and have significant milestones along the PV lifecycle

• Stage 1 - develop/finalize control strategy/plan

• Stage 2 - primarily concerned with achieving a level of confidence that the commercial process is working/implemented as planned, and on that basis, commercial distribution is justified

What is PV?

When is a process “validated”?

• Stage 3 - an effective quality unit will assure that systems and procedures are established to measure and characterize normal variability and process behavior, as well as to detect undesirable process variability from target quality parameters and control limits

• Investigations, risk assessments, and data!

What is PV?

New in ‘14

• New documents published since 2011 revision

• EMA Guideline on Process Validation (draft)

• PDA TR 60 – Process Validation: A Lifecycle Approach

• And many others…

What is PV?

“State of Control”

Stage 1

Monitor Collect

Assess

Stage 1 Stage 2 Stage 2

“State of Control” Goals

• Continual assurance that the process remains in a state of control

• Systems for detecting unplanned departures from the designed process are essential

• Variation in process performance is detected and evaluated

“State of Control” Control Systems

• Measured inputs, outputs, and disturbances

• Ability to set targets and evaluate error

• Hardware/software to transmit, organize, archive, and evaluate data

• Ability to control changes of state

“State of Control” (Advanced) Control Systems

• Platforms to analyze data between unit operations and down the process flow

• Decision making algorithms in automated process control environments

• Predictive technologies to “deliver the right information at the right time”

“State of Control” SPC Checklist

• How is data distributed, is it normal?

• What is the rational subgroup size?

• What is documented in SOPs?

• Establishing and revising control limits, magnitude of change, sampling (methods, linear time sequence, independence)

“State of Control” • Process Capability

• More short-term value

• Must be in state of statistical control

• Estimated using control chart methods and data

• Process Performance • More long-term value

• Estimated using standard formulas

Is the (actual) process capable?

Is the (actual) process stable?

Post-Approval Regulatory basis

Pharmaceutical cGMPs For The 21st Century – A Risk-Based Approach

“Encourage implementation of risk-based approaches that focus both industry and Agency

attention on critical areas”

Multi-District PoAIs

Post-Approval

• For FY13, a jointly developed initiative between CDER and ORA (Field Drug Committee)

• Evaluation of domestic firms identified via risk model (via PAI, regulatory history, manufacturing concerns, reporting, etc)

• In some cases considered “for-cause”

Multi-District PoAIs

• Primary areas of coverage

• PV (Stages 2 and 3)

• Major changes to production and/or control procedures

• Supplier qualification

• Laboratory, Quality Management

Post-Approval

Contract Manufacturing

• Many new applications have complex supply chains, declare multiple CMOs

• Increased supply chain complexity may increase Stage 3 complexity (inputs, outputs, and disturbances)

Post-Approval

Case #1: 100(a) for solid oral dosage

• Investigator observed inconsistent and non-uniform coating process

• Surface erosion on validation batches (w/o investigation…) including chipped, broken, and peeling tablets

• Lot was released, customer rejected lot

Case Studies

Case #1: 100(a) for solid oral dosage

• “Bad” tablets were removed, remaining “good” tablets sent to second customer

•Retain samples had surface erosion and faded imprints

• 100(a) equipment parameters and coating process not adequately understood and controlled

Case Studies

Case #1: 100(a) for solid oral dosage

“Without a thorough investigation to understand the root cause of coating defects (or hardness problems) proper corrective actions to prevent recurrence cannot be implemented. Repeated instances of sorting finished tablet lots to cull out defective tablets is indicative of your failure to assure your manufacturing processes are in a state of control.”

Case Studies

Case #2: 110(a) for solid oral dosage

• Investigator observed specification change controls for in-process blending, which lacked scientific rationale and justification

• From firm documentation, specifications were changed “from X to Y otherwise tablet might not pass assay”

Case Studies

Case #2: 110(a) for solid oral dosage

• Specifications changed back after firm experienced blend uniformity failures, change made without any scientific data

• 110(a) firm’s in-process controls were not adequate to establish sampling procedures, determine true process performance, and assure final product quality

Case Studies

Case #3: 165(d) for parenteral injection

• Investigator observed usage of sampling plans that were not representative of production batches

• Samples taken per lot were established and fixed, but were irrespective of lot size which was variable lot to lot.

Case Studies

Case #3: 165(d) for parenteral injection

• “[Your firm did not] reference a sampling plan that utilizes basic elements of statistical analysis or provide a scientific rationale for sampling that would vary the amount of samples taken according to the lot size. Your response does not define a confidence limit to ensure an accurate and representative sampling of the product.”

Case Studies

Combination Products

• 21 CFR 4, “CGMP Requirements for Combination Products”

• https://federalregister.gov/a/2013-01068

• How is PV interpreted when both 211 and 820 applies?

Case Studies

Combination Products

• Per 21 CFR 4.4(b)(1), 820.75 is not a “called out” provision in order to demonstrate compliance…

• …however, the validation of the device constituent part of the finished combination product will likely be evaluated on an inspection prior to approval

Case Studies

Top 10 TURBO 483 Drug Observations (21CFR211) for FY13

Case Studies

Drug Observation Trends

• No significant YOY change for top four Obs

• More Obs for 100(a) compared to 110(a)

• Increase in Obs for 113(b)

• Wasn’t top 20 Obs previous two FYs, was top Obs January-April 2013

• Compounding Pharmacy inspections

Case Studies

Top 10 TURBO 483 Device Observations (21CFR820/803) for FY13

Case Studies

Device Observation Trends

• CAPA establishment and documentation, two of top three Obs

• 75(a), PV for devices, approx same number of Obs as 100(b)

Case Studies

Summary • After design and development, validation by nature is confirmatory; you should have prior knowledge to evaluate your acceptance criteria

• The Agency recognizes and encourages the use of risk-based approaches, but they should be scientifically sound with the goal of achieving and maintaining a high level of product quality

Summary • Verification of thorough design, implementation, and performance is necessary to adequately validate an operation, system, or process

• Company culture and management buy-in are critical aspects for establishing a successful PV lifecycle working environment

• Acknowledgements

• OMPQ colleagues: Rick Friedman, Paula Katz, Grace McNally, and Mahesh Ramanadham

• Graphics: flickr CC, Presentation Magazine, stock.xchng, xkcd

• Contact information

• steven.hertz@fda.hhs.gov

• (301) 796-3203

Summary