Where Did Validation Come From?
- From disasters:
- 1971–7 deaths in USA
- 1972–5 deaths at Devenport Hospital,UK
- Began in 1970’s
- Originally sterilized based
- Now evolved into all Product, Process and Facility matters
What is Validation in Pharmaceutical or Definition of Validation Concepts?
- Validation is a term that comes from the word “valid” which means “can be justified or defended”
- Validation is demonstrating and documenting that something does (or is) what it is supposed to do(or be).
- Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. (Source-21CFR-Parts 820- Quality System Regulation-October 1996)
- Validation is an activity that involve establishing documented evidence that the systems, equipments, instruments facilities and processes do what they purport to do based on a plan, on other ways stating that validation is systematic approach to gathering and analyzing sufficient data that will give reasonable assurance (documented evidence), based on scientific judgment, that a process, when operating within specified parameters, will consistently & continuously produce results within predetermined specifications.
- Validation not only requires demonstration (or assurance) that the equipment meets it’s specs, but it also requires this demonstration to be documented.
- The mechanism for documenting a validation effort is called a protocol.
“Establishing the documented evidence which provides a high degree of assurance that a specific process will consistently produce a product of predetermined specifications and quality attributes.”
(As per FDA Guidelines 1987)
Definition (EU GMP):
“Action of proving, in accordance with the principles of Good Manufacturing Practice (GMP), that any procedure, process, equipment, material, activity or system actually leads to expected results.”
(As per EU GMP 1997)
Why Validation Required?
Validation is specifically referenced as a basic principle of GMP
Regulatory Issues: As well as ensuring acceptance by regulatory bodies and assuring Safe, Pure and Effective products, validation can reduce costs by reducing:
- Reliance on In-process controls
- Down time
When it goes wrong …..?
- Reliance on product testing
- Loss of confidence
- Possibility of adulterated products
- Inspection – “Observations” or “483’s”
Types of Validation:
A prospective validation programme is one that is implemented before the equipment or facility comes on stream, or before the product is manufactured.
A concurrent validation programme refers to the ongoing review and evaluation of prospective or retrospective validation data.
The initial validation which is not properly documented and whose historical data is to provide necessary guidance for the documentary evidence is termed as retrospective validation. The steps involved in this type of validation require preparation of a protocol, reporting the results of data review, leading to a conclusion and recommendation.
Revalidation provides the evidence that changes in a process and / or the process environment introduced either intentionally or unintentionally do not adversely affect process characteristics and product quality.
There are two basic categories of revalidation:
- Revalidation in case of known change (including transfer of processes from one site to another)
- Revalidation in case of Periodic revalidation carried out at scheduled intervals.
A system should be in place to ensure both situations are addressed. Documentation requirements will be the same as for the initial validation of the process and in many cases similar process validation protocols can be employed. The definition of what constitutes a change to a process or process environment needs to be agreed.
Possible reasons for starting the revalidation process include:
- The transfer of a product from one plant to another.
- Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality Viz.
- Changes in the plant
- Changes in product composition
- Changes in manufacturing process
- Changes in the packaging materials
- Change in vendor of RM/PM.
- Changes to computer systems
- Changes in the cleaning processes or agents
- Changes which may affect the quality and efficacy of product.
- The necessity of periodic checking of the validation results.
Periodic revalidation must be done to ensure that no unintentional changes were made and to prove that the results of the previous validation procedures are still valid.
The overall policy, intentions and approach to validation, including the followings but not limited:
- Facility/Area Qualification
- Utility (HVAC, Water System, Compressed Air System )
- Process validation
- Analytical Method
- Cleaning validation
- Control systems (e.g. Computer- Hardware, Software)
- Laboratory Instruments / Equipment
- Revalidation or Re-qualification
- Preventive maintenance
- Analyst Certification
- Change Control
- Annual Product Review
- Vendor Qualification
- Training of Personnel
- Temperature Mapping
- Hold Time Study
Validation is team effort that generally requires the involvement and close interaction of Quality Assurance, Production, Packaging and Engineering/Maintenance with other appropriate support such as R&D and Quality Control. The validation team should include representative’s from the mentioned departments to provide the necessary expertise and guidance.
The validation team comprises of key personnel, both internal and external consultants (based on the requirement) coordinate the overall validation process.
Validation team consists of personnel representing various technical back ground. The Validation Team may be made up of representatives from the following areas:
- Quality Assurance
- Quality Control
- Project & Engineering
- Out sourced agency / representative of Contract giver
Other personnel could be co-opted, as and when necessary.
Validation Includes The Preliminary Activities:
- Preparation of VMP (Validation Master Plan)
- Preparation of protocols
Preparation of Vmp & Protocols
The scope of VMP is to be describing the systems and methodology used to execute the various phases of the Qualification / Validation program. It applies to all critical equipment, instrumentation, utilities, procedures and other quality support systems used for manufacturing, processing, testing, labeling and packaging along with its relevant documentation.
By following the VMP document different protocols prepared.
The major portion of the validation activity shall be qualification of equipment, instrument and system which include:
- User Requirement Specifications (URS)
- Design Qualification (DQ)
- Factory Acceptance Test (FAT)
- Site Acceptance Test (SAT)
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
- Re-Qualification (RQ)
- Facility/Area qualification (AQ)
- Validation Reports (wherever applicable)
- Support Program Review: Routine calibration, Preventive maintenance, Periodic Performance Verification etc.
All Qualification/Validation activities will be performed based on protocol based approach. For all Qualification activity, before start of the activity a pre-approved protocol will be made available.
Qualification documents of Vendor are also acceptable in lieu of in house templates & documents. In such cases the qualification document provided by the respective vendor shall be reviewed by representative of user Department, QA and other departments if required.
The approach for qualification for new or applicable equipment/system are adopted by keeping the V-Model concept in the background. This approach is based on the philosophy that validation begins at the conceptual stage of a project and continues throughout the life of the system.
V-Model of Qualification
- User Requirement Specifications shall consist of Design Specifications and Functional Specifications.
Design Specification shall provide explicit information about the design requirements for equipment e.g. the dimensions, material of construction, layout, etc.
Functional Specification shall denote how each feature of the equipment/system must function
- The yellow boarder indicates that the User Requirement Specifications, which consist of design and functional specifications for the equipment, shall be verified with the actual equipment details (design and functional) offered by the Supplier. This is called Design Qualification and this is a documentation activity and recommended to be completed before the PO is placed.
- The left arm of the ‘V’ deals with defining the requirement and design of the equipment.
- The right arm of the ‘V’ ensures that for each item in the left arm, there is a corresponding activity which verifies the same in the equipment, these include:
- The installation is as per the design specifications in the URS (this activity is called IQ)
- The operation is as per the functional & design specifications in the URS (this activity is called OQ).
- The performance is as per the overall performance requirements specified in the URS (this activity is called PQ).
- FAT & SAT may be done based on the risk assessment of the equipment; it is not mandatory and hence, is shown with dotted lines.
- Each new stage of qualification shall be initiated after sign-off of the report of the preceding qualification stage.
- Vendor protocols for DQ/IQ/OQ/PQ, if found appropriate, shall be pre-approved and used as long as these documents are pre-approved.
- In case of elements that are such elements may be identified and executed vide a supplement to vendor documents. The vendor qualification documents shall be accepted as per pre-defined procedure defined.