FDA’s Guidance for Industry Process Validation: Impact Assessment

James Agalloco, Agalloco & Associates

FDA’s Validation Stages“This guidance describes the process validation activities in three stages.

Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.Stage 2 – Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.”

Some Initial ReactionThe document provides no insight into expected sample sizes, replicates, or any specifics regarding expectations for validation studies.It places the burden of proof on the industry to define appropriate methods for validation.The guidance expects objective scientific data supporting products / processes relying upon sound statistics. No statistical methods are identified.The guidance has no numerical requirements!Does not clearly address existing process and products and how to integrate them.

Major PointsGoal is to continually assure the process is properly defined initially and remains in a state of control over its operational life.Use of Statistics throughout the “life cycle”Design of Experiments to establish proven acceptable ranges (nothing new for many)PQ Level sampling until variability can be assessed (increased scrutiny necessary)Continued Process Verification – a clear expectation for SPC methods (OK, reconciliation with change control must be defined).

The Validation Life Cycle - circa 1993

Agalloco, J., "The Validation Life Cycle", Journal of Parenteral Science and Technology, Vol. 47, No. 3, p. 142-147, 1993.

What is the Core FDA Objective?Firms have to adhere to a set of practices that assure products are safe. These can be summarized by consideration of the following in all development & production activities:

Safety – Does no harm to the patientPurity – Free of contaminationEfficacy – Works as intendedIdentity – Is what its supposed to beStrength – Is stable over time

The product is The process only exists to make the product

It all takes place under CGMP

ProceduresTest methodsBatch Records

Impact on Sterilization & Aseptic Processing

Sterilization – Stage 1Process Design / Cycle Development

Component / Container MappingLoad MappingDetermination of material heat stabilitySelection of biological indicator

Equipment Qualification parallels guidance exactly.

Sterilization – Stage 2Performance Qualification parallels the guidance almost exactly, except …,The statistical component of the guidance doesn’t fit well at all. How many studies / runs are needed to initially qualify a sterilization cycle. Respect that many sterilization processes are validated using ‘worst case’ conditions and highly resistant BI’s, so are statistics really useful and/or necessary?

Sterilization – Stage 3Continuing Process Verification

Parameter MonitoringBioburden Monitoring Periodic CalibrationChange Control

Process, Materials, Equipment, etc.

Periodic re-qualification

All in all a good fit, except for expectations relative to the use of statistics.

Aseptic Processing – Stage 1Process Design / ???

Facility & equipment design / qualificationProcess design – aseptic controls are very different, and less certainSterilization processes – see prior slidesPersonnel influence – diminishing with isolators, but how to address in conventional manned environments

This is at best a force fit. Establishing relationships between controlled variables & outcomes is more complex than current models can address.

Aseptic Processing – Stage 2If you believe it can be validated at all, then the initial Performance Qualification parallels the guidance, except …,The statistical component of the guidance really doesn’t work with respect to parameters linking directly to performance.How many studies / runs are needed to initially qualify an aseptic process? Do statistics fit anywhere in an aseptic process?

Aseptic Processing – Stage 3Continuing Process Verification

Parameter Monitoring – EM, HVAC? Maybe not!Periodic Calibration -Change Control

Process, Materials, Equipment, etc.

Periodic re-qualificationWhat about the human factor?

A reasonable fit, if we ignore the human influence, and ignore statistics. But that’s what the guidance is all about.

Implications for Sterilization & APSome substantial clarification is needed to reconcile the draft guidance with sterile products validationSterilization works to some extent, but the DOE & statistical elements are problematic.Aseptic processing must be force fit into conformance with the guidance. It has the same problems as sterilization, plus the human factor will present unique problems in application.

Understanding Industry Reaction

☺ Those firms with well-founded validation programs and solid development will welcome the guidance as it allows for flexibility of approach driven by good science.

Firms with less evolved development / validation activities will complain about the lack of definition and open ended nature of the guidance, they expected more well defined requirements.

PDA Membership Concerns - 1How to address previously validated product, processes & systems?A glossary of terms is needed.Clarification of scope – where applied

Clinical, sterilization, cleaning, etc?

Level of assurance required to initiate commercial product release.Clarification of the expectations for concurrent release of batches.

PDA Membership Concerns - 2Viral and Impurity Clearance studies under CGMP?Clarification of equipment, utility, and facility qualification expectations.Clarification of documentation expectations, including use of plans and protocols.Clarification of regulatory submission, reporting impact, and inspection expectations.Levels of testing required for Continuous process verification. Should FDA or industry provide these answers?

What Does it All Mean?Continued confusion on the part of many in industry / FDA with respect to expectations.Opportunities for good science to prevail, rather than arbitrary dictates

Statistics replacing “the rule of three”

An era of hybrid validation programs for products on the market and already in development.An eventual clarity of validation requirements in many areas.

Conclusions & RecommendationsThe qualification / validation model in the guidance is fully applicable to validation of products / processes, but only partially to sterilization & aseptic processing.A extensive effort to provide a common level of expectations between FDA & Industry (as well as within FDA & industry) is urgently needed.A revision / update of FDA’s 1994 Submission Guidance for Sterile Products might be the best way to address the desired approaches for the validation of sterilization procedures and aseptic processing.

• increased throughput• reduction in rejections and reworks• reduction in utility costs• avoidance of capital expenditures• fewer complaints about process related failures• reduced testing - in process and finished goods• more rapid / accurate investigations into process

upsets• more rapid and reliable startup of new equipment• easier scale-up from development work• easier maintenance of the equipment• improved employee awareness of processes• more rapid automation

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Post-Script: Benefits of Validation

THE BENEFITS ARE REAL!