Verification and Validation applied to dietary

supplement manufacturing process

Laura Liu
NSF International

Agenda

Regulation requirement

Definition in the international standard

Why to use verification and validation
Key concept for the understanding
The implementation for dietary supplement quality control system during
production

DS regulatory status internationally

In between food and pharmaceuticals

Food

DS

Pharm

2 V application in food and pharm industry

The terminology widely used in regulatory guideline and quality management

system of food and pharmaceutical industry.

ISO 9001
ICHQ10
HACCP (risk based food safety management system)
SQF

Regulation for dietary supplement (21CFR)

Verification is included
111.75
Conduct at least one appropriate test or examination to verify the
identity of any component that is a dietary ingredient,..
You must select one or more established specifications for
identity, purity, strength, composition,. would verify that the
production and process control system.

Regulation for dietary supplement (21CFR)

No direct and explicit validation included, but:

111.70 You must provide adequate documentation of your basis for why meeting
the in process spec.will help ensure that the spec are met for of the dietary
supplement
111.75 (c) For a subset of finished dietary supplement batches that you identify
through a sound statistical sampling plan (or for every finished batch), you must
verify that your finished batch of the dietary supplement meets product
specifications

FDA guideline for drug - Process validation

Process validation:

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 products.

Codex for food(HACCP)

Verification: The application of methods, procedures, tests and other evaluations,

in addition to monitoring to determine compliance with the HACCP plan.
Validation: Obtaining evidence that the elements of the HACCP plan are effective.

SQF(Safe Quality Food)

Verification: Essentially verification as applied to control measures seeks to prove

that the control measure was done according to its design.
Validation: Essentially validation as applied to control limits seeks to prove that the
intended result was achieved and that it actually worked.

Why to use verification and validation in the quality related system

To evaluate whether the operations associated with product and the process
designed for system accomplishment is well implemented as planned.
To evaluate whether the operations, the quality control plan and management
system implemented is effective to ensure the product meet the intended needs
To achieve the continued improvement

Verification

Verification

Is the control plan followed as written?

Scheduled & systematic?
Trained, designated employees?
Operations or control measures implemented as instructed?

Core Concept: is Followed

Validation

Validation
Is the control measures or system effective to ensure the
quality?

A serials proof and documentation that the process or plan

works well to ensure the product meet the specification

Core Concept: is Effective

Verification and Validation

Verification could be part of the process of validation
Validation is needed for some critical processes when:
The verified measurements can't easily be done on routine
production; or (for example, the contaminants test)
the verifications are not sufficient because the method is
destructive
The tests are performed by sampling, not 100%
Some tests lack the sensitivity
Lower the cost by partial verification

Quality cant be adequately assured

merely by in process and finished product
inspection or testing. US FDA

Verification

Major Elements of Verification

Understanding monitoring procedures

Ensuring monitoring procedures being performed by trained individuals
Activities including observation, or check, test, or records review
Recording at the time of performance
Verification for monitoring of Quality Control Plan, Cleaning and Sanitizing
activities and the implementation of related SOPs

Validation process

Validation process: a systemic approaches and activities to prove that the

intended result was achieved and that it actually worked

Personnel --trained, qualified

Equipment --qualification
Procedure or methods -- science based, reviewed and approved
Materials -- specification compliance, approved supplier
Environment -- appropriate

The implementation of verification and validation in the production

Step1: Identify which stages or points to be verified and validated

Step2: Develop the verification and Validation Plan applied to
control system

Which stages or points to be verified and validated

Risk based approaches: high risk or critical to quality

Quality risk management tool:

FMEA(Failure Mode and Effective Analysis)
HACCP(Hazard Analysis Critical Control Point)

Master Verification & Validation plan

Develop verification and validation process

Purpose (why?)
Identify activities (what?)
Methods (how?)
Frequency (when?)
Responsibility (who?)

Dietary Supplement typical production flow

Materials and
Ingredients
receipt

Manufacturing

Packaging

Labeling

Holding

 Luckily, the regulation regarding quality and safety issued by the regulator
(mostly FDA in most of country) based on risk evaluation and critical process
has identified general critical processes.
Nevertheless, specific measures to the plant specific processes and
equipments still need to be developed by the manufacturer

Regulation requirements for the raw materials (FDA 21CFR111)

Establish the specification

Determine whether the specifications are met

A quarantine control system in place for the rejected components

Quality control for raw material

Establish the specification for all raw materials

Establish the supplier requirements

Evaluate the potential suppliers
Examine raw materials and re-evaluate the suppliers

Quality control for raw material

Risk based approaches

Risk considerations (SIDI)
Type of component
Suppliers quality system
Suppliers upstream controls (e.g., its supplier qualification
process)
Supplier history and reputation
Country / region of origin
Regulatory status (GRAS, new dietary ingredient, etc.
Known economically motivated adulterants?
Financial stability of supplier

Quality control for raw material

Type of Component:
Ingredient
Plant
marine- or animal-based
chemical

Excipient:
Processing aids
Product contact packaging materials
Non product contact packaging materials

Quality control for raw material

Components specification can be derived from

USP monograph
Regulatory requirement
Vendors COA
Client input/requirements
Intended uses
Others: quality System requirements, quantities, timing,
etc

Supplier qualification
Evaluate potential suppliers
Vs. your specifications
Vs. quality system requirements
Vs. other requirements

Some help from supplier qualification guideline-SIDI

Appendix 1 SIDI protocol
Appendix 2 and 3 (templates)

Verification activities

Verification activities for the components kept under

control
What: formal protocol or written procedures , approved supplier list
, Suppliers re-qualification documentation, suppliers COA etc.
When: frequent quality check, each batch received
Who: trained quality person
How: Visual check for the monitoring activities, sampling, testing,
documentation review

Validation Process

Validation activities
Review of rejections at receiving
Consumer complaints review
Observe and review Receiving protocol (Letters of
Guarantee, CoAs, Quality system documents )
Incoming raw materials testing reports
Field audit for the supplier

Manufacturing process

111.70 You must establish a specification for any point, step, or stage in
the manufacturing process where control is necessary to ensure the
quality of the dietary supplement.
Identify the critical process or operation to quality for the entire
stages of production using risk analysis tools

Manufacturing process

Normally, the Critical to Quality steps or points:

Heating steps
Cooling steps
Product formulation control steps
Blending for multi trace nutrients
Filling
Points where specific cleaning and sanitation needed
Points where cross contamination may occur
Steps where employee and environmental hygiene are necessary

Manufacturing process

Verification activities for the phase of process evaluation:

SOPs in place for equipments on operation, cleaning and sanitation,
maintenance
Responsible personnel well trained and qualified
Quality operation procedures or control plan
Testing methods
Master manufacturing record

Manufacturing process

Ongoing verification.

Calibration review of process-monitoring instruments

Direct observations of monitoring and corrective actions
BMR (Batch Manufacturing records)
Testing report
COA
Product release records

Manufacturing process
Validation activities prior to the commercial production

Process qualification protocol review

R&D studies including lab studies and pilot studies
Several batches manufacturing records and monitoring records
Sampling plan
Testing method
Testing result review and statistical analysis
Verification activities noted previously (SOP, testing method, etc)
Documentation for the protocol completion( Data analysis,
Deviation review, conclusion)

Manufacturing Process
Ongoing validation activities for production:

Critical equipment requalification or necessary calibration

Testing and Analysis for all attributes to quality specification
Product complaints
Product audit
Manufacturing process
Process deviation, or OOS trend analysis
Production data collected to evaluate the process stability

Summary

In common that verification and validation has

A planned and organized program for product and process at all
stages
Performed by the qualified person
Ongoing process
Requirement for records

Summary
Verification
Who performs verification activities?
Designated and well trained person
Independent professional of the operator
What to verify?
Records, documents, test result, corrective actions, performance
When to verify?
Daily monitoring records, corrective actions and product
evaluations, performance
Incidentally change in product or process
Frequently monthly inspection, internal inspection or audit

Summary
Validation
Who performs validation activities?
Trained, qualified team member
Independent professional
What to validate?
In process product and finished product meet the specification determined.
Process deviation
Complaints
Audit result
When to validate?
Prior to control Plan and MMR implementation
Change in process, product, system failure
Annually at minimum

Thank you
Laura Liu, PhD
Health Science Division
NSF International (China Office)

E-mail: lliu@nsf.org
Web: www.nsf.org