New EU Requirements for Qualification & Validation

February 2, 2023July 13, 2019 by Pharmaceutical Guidanace

New EU Requirements for Qualification & Validation

Updated version of Annex 15 ◦ Qualification and Validation

Draft released in February 2014

Final version released on the 30th of March , 2015

Will be effective on 01 October 2015 4/3/2015 3

Improved Annex 15

May be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II.

Retrospective validation is no longer an acceptable approach

The term “validation” has been replaced with “qualification and validation” to reflect the true intent of the Annex 15 in several instances.

An “equivalent document” to a VMP may be used for qualification and validation planning

VMP no longer needs to include –

Protocol and report templates,
scheduling and planning information
Confirmation of materials and suppliers used

For large and complex projects separate validation plans may be used

The importance of Quality Risk Management is evident
Risk assessment to be repeated if further knowledge and understanding is gained from any changes during the project phase or during commercial production.
Data integrity is also mentioned were “appropriate checks” needs to be built into qualification and validation tasks “to ensure the integrity of all data obtained”.

Current version of Annex 15 of the EU Guide to GMP

Originally published in September 2001
Significant changes in the GMP environment
Advancements in manufacturing technology and continuous manufacture processes.
Many changes to other Chapters and Annexes which have an impact on Annex 15
Current version of the US FDA Guide on Process Validation,
Approaches in ASTM E2500-07 “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Bio-pharmaceutical Manufacturing Systems and Equipment “
All the above has justified the change.

This revision to Annex 15 takes into account

Changes to Other sections of the EudraLex, Volume 4, Part I ◦ Relationship to Part II
Annex 11
ICH Q8, Q9, Q10 and Q11
QWP guidance on process validation
Changes in manufacturing technology

Annex describes

Principles of Qualification and Validation

Applicable to

Facilities
Equipment
Utilities and processes
Manufacture of medicinal products

May also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II.

Qualification & Validation

GMP requirement
Control critical aspects of particular operations
Applicable over the life cycle of product and process
Document any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, and the impact on the validated status or control strategy assessed.

Qualification & Validation

Validate computerised systems :Annex 11.
Use concepts and guidance of ICH Q8, Q9, Q10 and Q11.
Apply quality risk management approach throughout the lifecycle
Determine scope and extent of qualification and validation on risk assessment of the facilities, equipment, utilities and processes.
Document the risk assessment
Retrospective validation is no longer considered an acceptable approach.
Data obtained from sources outside of the manufacturers own programmes
May be used
Justify this approach
Adequate assurance that controls were in place throughout the acquisition of such data.

Organising and Planing

Plan all activities
Implement the life cycle approach
Consider
Facilities
Equipment
Utilities
Process
Product
Performed by suitably trained personnel
Follow approved procedures
Qualification/validation personnel should report as defined in the pharmaceutical quality system
Not essential to be a quality management or a quality assurance function.
Appropriate quality oversight over the whole validation life cycle is essential.
Define key elements of the site qualification and validation
Document in a validation master plan (VMP) or equivalent document.
VMP or equivalent document
Define qualification/validation system

Include or reference information on at least the following:

Qualification and Validation policy
Organisational structure
Roles and responsibilities for qualification and validation activities.
Summary of the facilities, equipment, systems, processes on site
Qualification and validation status
Change control and deviation management for qualification and validation
Guidance on developing acceptance criteria
References to existing documents
Strategy, including re-qualification, where applicable.
For large and complex projects,
Added importance to planning
Separate validation plans may enhance clarity.
Use quality risk management approach
Repeat Risk assessment with increased knowledge & Changes
Project Phase
Commercial Phase
Document the way in which risk assessments are used
Incorporate appropriate checks
Ensure the integrity of all data obtained.

Documents Include VMP:

Good Documentation Practices

Important to support knowledge management.
Implement throughout the product lifecycle
All documents should be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system.
Define the inter-relationship between documents in complex validation projects
Prepare validation protocols which defines the critical systems, attributes and parameters and the associated acceptance criteria.
Documents may be combined together, where appropriate
e.g. installation qualification (IQ) and operational qualification (OQ).
Any significant changes to the approved protocol during execution
Acceptance criteria
Operating parameters
Document as a deviation
Justify scientifically.
Record results not meeting pre-defined acceptance criteria as a deviation
Investigate all devotions
Discuss any implications for the validation in the report .
Each stage should have a formal release before proceeding to next stage
Release should be authorised by relevant responsible personnel
Release may be a part of validation report or as a separate summary document
Conditional approval to proceed to the next qualification stage possible when
Certain acceptance criteria or deviations have not been fully addressed
There is a documented assessment that there is no significant impact on the next activity.

Qualification Stage for Equipment,Facility,Utilities and system

Qualification activities

Consider all stages

Initial development of the user requirements specification through to End of use of the equipment, facility, utility or system.

The main stages and some suggested criteria which could be included in each stage are indicated in subsequent slides:although this depends on individual project circumstances and may be different.

User requirements specification (URS)

Define specification in a URS and/or a functional specification for

Equipment
Facilities
Utilities or systems
The essential elements of quality need to be built in at this stage
GMP risks if any should be mitigated to an acceptable level.
URS should be a point of reference throughout the validation life cycle.

Design qualification (DQ)

The next element in the qualification of equipment, facilities, utilities, or systems.
Demonstrate compliance of the design with GMP
Document compliance
Verify requirements of the user requirements specification during the design qualification.

Factory acceptance testing (FAT) /Site acceptance testing (SAT)

Equipment may be evaluated at the vendor prior to delivery.
Confirm compliance with URS/functional specification prior to installation at the vendor site
Documentation review & some tests could be performed at the FAT or other stages
These tests need not be repeated on site at IQ/OQ if functionality is not affected by transport and installation.
FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.

Installation qualification (IQ)

Perform IQ on

Equipment

Facilities

Utilities

Systems.

IQ should include, but is not limited to the following:

Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications;
Verification of the correct installation against pre-defined criteria;
Collection and collation of supplier operating and working instructions and maintenance requirements;
Calibration of instrumentation
Verification of the materials of construction.

Operational qualification (OQ)

OQ normally follows IQ
May be performed as a combined Installation/Operation Qualification (IOQ).
Depends on the complexity of the equipment.

OQ should include but is not limited to the following:

Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed;

Tests to confirm upper and lower operating limits, and /or “worst case” conditions.

Performance qualification (PQ)

PQ should normally follow the successful completion of IQ and OQ.

Could also be performed in conjunction with OQ or Process Validation.

PQ should include, but is not limited to the following:

Tests using
Production materials,
Qualified substitutes or
Simulated product proven to have equivalent behaviour
Normal operating conditions
Worst case batch sizes.
Justify the frequency of sampling used to confirm process control
Tests should cover the operating range of the intended process
No need for this if documented evidence from the development phases confirming the operational ranges is available.

RE-QUALIFICATION

Evaluate at an appropriate frequency to confirm that following remain in a state of control

Equipment
Facilities
Utilities
Systems

Justify re-qualification period

Define criteria for reevaluation

Assess the possibility of small changes over time.

Process Validation

General Principles

Applicable to the manufacture of all pharmaceutical dosage forms.
Initial validation of new processes
Subsequent validation of modified processes
Site transfers and ongoing process verification.
Robust product development process required to enable successful process validation.
This guidance should be used in conjunction with the current EMA guideline on Process Validation for Finished Products.
Guidance on information and data to be provided in the regulatory submission only.
However GMP requirements for process validation continue throughout the lifecycle of the process.
Apply this approach to link product and process development.
Manufacturing processes may be developed using a
Traditional approach
Continuous verification approach
Before any product is released to the market & irrespective of the approach used
Processes must be shown to be robust
Ensure consistent product quality.

Traditional approach

Only prospective validation programme prior to certification of the product.
Retrospective validation is no longer an acceptable approach.

New products

Cover all intended marketed strengths
Cover all sites of manufacture
Bracketing could be used. Justify based on,1. Extensive process knowledge from the development stage,2. An appropriate ongoing verification programme

Site Transfer

Transferred from one site to another
Within the same site
Number of validation batches could be reduced by the use of a bracketing approach. Justify based on
Existing product knowledge,
Content of the previous validation

Use bracketing for

Different strengths
Batch sizes
Pack sizes
Container types

Site Transfer of Legacy products

Manufacturing process and controls must comply with the marketing authorisation
Meet current standards for marketing authorisation for that product type.
If necessary, variations to the marketing authorisation should be submitted.

Attributes and parameters

Important for ensuring the validated state and acceptable product quality
Process validation should establish whether these can be consistently met by the process
Document the basis for identifying criticality of parameters & attributes.

Process validation batches

Same size as the intended commercial scale batches
Justify use of any other batch size

Development studies & Process knowledge

Basis of all validation activities
For all products
Irrespective of validation
Should be accessible to the manufacturing site,
Other wise justify

General Principles

Process validation batches
Production personnel
Development personnel
Other site transfer personnel
Use only trained personnel
Manufacture in accordance with GMP
Use approved documentation
Production personnel should facilitate product understanding.
Qualify suppliers of critical starting and packaging materials prior to manufacture
Otherwise
Justify based on of quality risk management principles
Document justification

Design Space & Mathematical Models

Could be used for Process control strategy

Following should be available

Underlying process knowledge
Development of any mathematical models
Justification

Release of Validation batches to the Market

Pre-define
Manufacture should fully comply with
GMP
Validation acceptance criteria
Continuous process verification criteria (if used)
Marketing authorisation
Clinical trial authorisation.

Investigational medicinal products (IMP),

Refer to Annex 13.

Concurrent validation

Routine production starts before completion of validation
Concurrent validation can be used under exceptional circumstances
A strong benefit-risk ratio for the patient required
Justify decision to carry out concurrent validation
Document the decision in the VMP for visibility
Decision should be approved by authorised personnel
Have sufficient data to support a conclusion that
Any given batch of product is uniform
Meets the defined acceptance criteria.
Document the results and conclusion formally
Document should be available to the Qualified Person prior to certification of the batch.

Traditional process validation

Number of batches of the finished product are manufactured under routine conditions to confirm re-producibility
Number of batches manufactured & Number of samples taken
Use Quality Risk Management principles
Allow the normal range of variation and trends to be established
Provide sufficient data for evaluation.
Number of batches manufactured & Number of samples taken
Determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.

Generally acceptable

Without prejudice to earlier requirement
Minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process.
Alternative number of batches may be justified based on
Whether standard methods of manufacture are used
Whether similar products or processes are already used at the site.
Supplement an initial validation exercise with three batches with further data obtained from subsequent batches as part of an on-going process verification exercise.
Process validation protocol should be prepared which defines
Critical process parameters (CPP),
Critical quality attributes (CQA)
Associated acceptance criteria
Base this on development data or documented process knowledge.
Process validation protocols should include, but are not limited to the following:

1. A short description of the process and a reference to the respective Master Batch Record;

2. Functions and responsibilities;

3. Summary of the CQAs to be investigated;

4. Summary of CPPs and their associated limits;

Process validation protocols should include, but are not limited to the following:

Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion;
List of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status;
List of analytical methods and method validation, as appropriate
Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected;
Additional testing to be carried out with acceptance criteria;
Sampling plan and the rationale behind it;
Methods for recording and evaluating results;
Process for release and certification of batches (if applicable)

Continuous process verification

Can be used as an alternate approach for traditional process validation for
Products developed by a quality by design approach
Scientifically established control strategy during development
A strategy which provides a high degree of assurance of product quality .
Define the method by which the process will be verified
Put in place a science based control strategy for the required attributes to confirm product realisation for
Incoming materials
Critical quality attributes
Critical process parameters
Put in place a science based control strategy for the required attributes to confirm product realisation
Include regular evaluation of the control strategy.
Process Analytical Technology and multivariate statistical process control may be used as tools.
Determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.
The general principles presented earlier still apply.

Hybrid approach

A hybrid of the traditional approach and continuous process verification approach
Could be used where there is
Substantial amount of product and process knowledge
Understanding which has been gained from manufacturing experience and historical batch data.
Could be used
Even if the product was initially validated using a traditional approach
For any validation activities after changes
During ongoing process verification.

Ongoing Process Verification during Lifecycle

 Applicable to all three approaches to process validation mentioned earlier, i.e.Traditional, Continuous or Hybrid.
Monitor product quality
Ensure that a state of control is maintained throughout the product lifecycle
Evaluate relevant process trends
Periodically review extent and frequency of ongoing process verification.
Any point during the life cycle appropriate to modify the requirements taking into account the current level of process understanding and process performance.
Conduct under an approved protocol or equivalent documents
Prepare a corresponding report
Document the results obtained
Use Statistical tools to support any conclusions of variability and capability of a process
Ensure a state of control.
Use throughout the product lifecycle
Support the validated status of the product as documented in the Product Quality Review.
Consider
Incremental changes over time
Need for any additional actions,
e.g. enhanced sampling, should be assessed.

Verification of transportation

Applicable to
Finished medicinal products
Investigational medicinal products
Bulk product
Samples

Above should be transported as defined in the

Marketing authorisation
the approved label
product specification file
As justified by the manufacturer
Challenging due to the variable factors involved
Define transportation routes clearly
Consider seasonal and other variations during verification
Perform a risk assessment Considering
Impact of variables
Transportation process
Conditions which are continuously controlled or monitored,
Delays during transportation
Failure of monitoring devices
Topping up liquid nitrogen
Product susceptibility
Any other relevant factors
Variable conditions are expected during transportation
Therefore perform continuous monitoring & recording of critical environmental conditions
Justify if this is not done
Document the justification

Validation of Packing

Qualify primary and secondary packaging equipment for finished and bulk products
Variation in equipment processing parameters
These have significant impact on the integrity and correct functioning of the pack,
Blister strips, sachets and sterile components, therefore
Qualify primary packing equipment
Qualify the minimum and maximum operating ranges defined for the critical process parameters
Temperature
Machine speed
Sealing pressure
Any other factors

Qualification of Utilities

Perform qualification using the qualification steps described earlier following

Steam
Water
Air
Other gases
Qualification – Should reflect any seasonal variations and Intended use of the utility.
Perform a risk assessment if there could be direct or indirect contact with the product,
Heating, ventilation and air-conditioning (HVAC) systems
Through heat exchangers
Mitigate any risks of failure

Validation of Test Method

Validate all analytical test methods used in

Qualification
Validation
Cleaning exercises
Validate with an appropriate detection and quantification limit
as defined in Chapter 6 of the EudraLex, Volume 4, Part I.

Microbial testing of product

Validate method to confirm that the product does not influence the recovery of microorganisms.
Microbial testing of surfaces in clean rooms
Perform validation to confirm that sanitizing agents do not influence the recovery of microorganisms.

Cleaning Validation

Perform cleaning validation
Confirm the effectiveness of all cleaning procedure for all product contact equipment.
Simulating agents may be used with appropriate scientific justification.
Similar types of equipment may be grouped together
Provide a justification of the specific equipment selected for cleaning validation.
Visual check for cleanliness is an important part of the acceptance criteria
Do not use this criterion alone
Do not repeat cleaning and retesting until acceptable residue results are obtained
not considered an acceptable approach.
Programme may take some time to complete
Validation with verification after each batch may be required for some products,
e.g. investigational medicinal products.
Collect sufficient data from verification to support a conclusion that the equipment is clean and available for further use.
Validation should consider
Level of automation in the cleaning process.
Automatic process
Validate the specified normal operating range of the utilities and equipment
Perform assessment of all cleaning processes
Determine variable factors which influence cleaning effectiveness and performance
Operators
Level of detail in procedures such as rinsing times etc.
Use worst case situations for cleaning validation studies identified.
Limits for the carryover of product residues should be based on a toxicological evaluation
Document justification in a risk assessment
Include all the supporting references.
Establish limits for the removal of any cleaning agents used.
Consider the potential cumulative effect of multiple items of equipment in the process equipment train to determine acceptance criteria.
Limits for the carryover of product residues should be based on a toxicological evaluation
Therapeutic macro-molecules and peptides degrade and denature (when exposed to pH extremes and/or heat).
May become pharmacologically inactive.
A toxicological evaluation may therefore not be applicable in these circumstances.
Limits for the carryover of product residues should be based on a toxicological evaluation
When testing for specific product residues is not feasible other representative parameters may be selected
Total organic carbon (TOC)
Conductivity

Consider the risk presented by

Microbial contamination
Endotoxin contamination

Consider Influence of the time

between manufacture and cleaning
between cleaning and use
Based on this define for the cleaning process
Dirty hold time
Clean hold time

For campaign manufacture consider

Impact on the ease of cleaning at the end of the campaign
Maximum length of a campaign (in time and/or number of batches)

Worst case product approach

Provide a scientific rationale for

Selection of the worst case product
Impact of new products to the site assessed

Criteria for determining worst case

Solubility
Cleanability
Toxicity
Potency

Cleaning validation protocols

Specify or reference the locations to be sampled
Rationale for the selection of these locations
Define the acceptance criteria

Sampling

Swabbing
Rinsing
Other means depending on the production equipment.
Sampling materials and method should not influence the result.
Demonstrate recovery from all product contact materials sampled in the equipment with all the sampling methods used.

Cleaning procedure

Perform an appropriate number of times
Base this on a risk assessment
Meet the acceptance criteria in order to prove that the cleaning method is validated

Cleaning process

Ineffective
Not appropriate for some equipment

Use

Dedicated equipment
Other appropriate measures for each product
Refer chapters 3 and 5 of EudraLex, Volume 4, Part I.

Manual cleaning of equipment

Confirm effectiveness of the manual process at a justified frequency.

Change Control

Control of change

Important part of knowledge management
Handle within the pharmaceutical quality system

Put written procedures in place & describe the actions to be taken if a planned change is proposed to

Starting material
Product component
Process
Equipment
Premises
Product range
Method of production or testing
Batch size
Design space
Any other change during the lifecycle that may affect product quality or reproducibility.
When Design space is used ,Consider the impact on changes to the design space as registered in M A ,Assess need for any regulatory actions.

Use Quality Risk Management to evaluate planned changes to determine the potential impact on

Product quality
Pharmaceutical quality systems
Documentation
Validation
Regulatory status
Calibration
Maintenance
Any other system
Avoid unintended consequences
Plan for any necessary process validation, verification or re-qualification efforts.

Changes

Authorised
Approved
Responsible persons
Relevant functional personnel
Follow the pharmaceutical quality system.
Review supporting data
Confirm impact of change has been demonstrated prior to final approval.
Perform an evaluation of the effectiveness of change
Confirm that the change has been successful

New EU Requirements for Qualification & Validation

References: New EU Requirements for Qualification & Validation by GMP EDUCATION: Not for Profit Organization