FDA Process Validation

Purpose

1. The purpose of the Federal Drug Administration's process validation procedures, according to the FDA, is to establish "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 characteristics." The guidelines issued by the FDA pertain to pharmaceuticals and medical devices.

Quality Assurance

2. To ensure quality, FDA guidelines state that "quality, safety and effectiveness must be designed and built into the product, quality cannot be inspected or tested into the finished product and each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications." The goal of quality assurance is to produce goods that work as they are intended to.

Process Validation

3. Process validation is key to meeting standards that will lead to FDA approval of a product. Carefully designing both the process and the process controls can reduce dependence on finished product testing, though end-product testing is important and required. To this end, the manufacturer must produce a written validation protocol that identifies the procedures and tests that will be performed, the data that will be collected, the purpose of collecting the data, the number of replicate process runs to be performed that will demonstrate reproducibility, and a way to measure variability in successive runs. The variability measurement must take into account "processing limits and circumstances" that would result in the greatest chance of process or product failures, such as machines going down, changes in environmentals or other scenarios that can affect the manufacture of the product outside of optimal conditions.

Pharmaceuticals

4. For pharmaceuticals, "there shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess." There must also be control procedures that monitor the output and validate the processes that cause variability in the drug product. There must also be written procedures designed to prevent microbiological contamination of the product.

Medical Devices

5. For medical devices, it is required that "written manufacturing specifications and processing procedures shall be established, implemented and controlled to assure that the device conforms to its original design or any approved changes in that design." The goal is to ensure that the manufacturing process has sufficient control measures to consistently produce a product that is in keeping with the approved design product characteristics.

Elements of Process Validation

6. The FDA lists the following as the required elements for proper process validation. Prospective validation must take into account changes in manufacturing processes that can affect product characteristics and includes the equipment used in the manufacture, the testing used to determine that the product consistently performs as designed, and product testing to ensure that the process used to produce the product does not adversely affect the finished product. A formal technical review should also be conducted to compare the approved product specifications with the actual product, validate the testing procedures and determine if the change-control program is adequate. It is imperative that the validation program is sufficiently documented and maintained.

Validation-related Issues

Approach to validation
SOPs
Calibration
Environmental monitoring
Preventive maintenance
Training
Raw material sampling and qualification programs
Change control
Facilities/systems
Manufacturing/packaging methods
Formulations
Raw materials & Suppliers
Cleaning Procedures
Computer and control systems
• Problems seen recently are similar to ones in past
• Validation issues - one of top two reasons for
deficiency notices
– Protocols are not followed
– Inadequate (insufficient testing, lack of specs, etc.)
– Retrospective validation - changes occurred within
sequence
– Inadequate change control, revalidation program
– Older products - bringing up-to-date is difficult

General Notes on Validation

• Validation batches are saleable and
therefore will be used by patients.
True validation batches mimic routine
production in every detail. For example,
– Material handling methods of feeding a
tablet press may affect the processability.
– Batches should be ‘QC releasable’. We are
validating ‘acceptable’ processing and
product.
Note: Data from unacceptable batches may in special cases support
validation
• Sampling is frequently an issue in validation.
– Thus, think and plan ahead on specifics of the number
of samples, sample size, sampling location, method,
and handling and who will perform what activity
– Also, sample in the same way as development,
demonstration or prevalidation batches.
• Sampling strategy can be as important as process
development.
• Following protocols and procedures is another
frequent issue in validation.
– Consult the protocol and procedures frequently to be
sure they are being followed.
• Know your equipment, process parameters,
materials, tests and expected results.
• A robust process will allow some normal variation
in equipment operation, raw materials, and other
variables (e.g. environmental)
• Deviations and OOS (out-of-specification) results can jeopardize a
successful process validation.
• The development and production history can be helpful in
investigations.
• Conduct scientific and thorough investigations. Write clearly.
Implement corrective actions.
• Quality cannot be inspected or tested into the product; i.e. repeat
testing and resampling will not improve the quality.
• Quality comes through designing and proper controls of
manufacturing parameters (build quality into product).

Validation Protocol

1. General information
2. Objective
3. Background/Prevalidation Activities
Summary of development and tech transfer (from R&D or another
site) activities to justify in-process testing and controls; any
previous validations.
4. List of equipment and their qualification status
5. Facilities qualification
6. Process flow chart
7. Manufacturing procedure narrative
8. List of critical processing parameters and critical excipients
9. Sampling, tests and specifications
10. Acceptance criteria
Reference to: Stability protocol/packages, protocol change provisions
(i.e., procedures to handle any deviations), plans for a biobatch comparison
(formula, process, specifications)

Validation Checklist

Validated analytical methods for registered in-process and final
product testing
Raw materials meet specifications; Drug substance is validated and
fully characterized; at least 2 separate lots from vendor
Facilities and equipment are qualified and calibration and PM
programs are in place
Key process variables are identified and their operating ranges have
been established
Finalized master batch record
Relevant SOPs are in place and training is completed on equipment
operation, manufacturing instructions, and sampling strategy.
Quality Systems such as deviations, change control, site Quality
Review Committee are in place

Validation Responsibilities

Colleagues to administer program
- e.g. Technical Services or Site
Validation Committee (SVC)*
– Develop site master validation plan.
– Prepare/execute/approve validation studies.
Manufacturing Operations prepares the batches as though they are
routine production batches.

QA ensures compliance and that documentation and procedures
are in place. Approves protocols and reports.

QC Laboratories - performs testing or contracts validation testing.
Reviews protocols and reports as needed.

Types of Validation

Prospective -
At least three successive production-size (US view)
batches, all batches made, tested, and report approved before
distribution, facilities and equipment qualified
Concurrent -
Generation of validation data concurrent or
simultaneously with normal production schedules. Used in exceptional
cases (low volume products); interim reports required.
Retrospective -
based upon accumulated manufacturing, testing, and
control batch data (EU Annex 15); least preferred approach (used
typically for mature products), no changes during period, assess critical
test results of at least 20 batches