New EU Requirements for Qualification & Validation

New EU Requirements for Qualification & Validation

An 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

It may be used as supplementary optional guidance for active substances without introducing 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 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 is to be repeated if further knowledge and understanding is gained from any changes during the project phase or commercial production.
  •  Data integrity is also mentioned where “appropriate checks” need to be built into qualification and validation tasks “to ensure the integrity of all data obtained”.

The 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 manufacturing processes.
  • Many changes to other Chapters and Annexes which have an impact on Annex 15
  • The 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 the 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, that may affect the quality of the product, and the impact on the validated status or control strategy assessed.

Qualification & Validation

  • Validate computerized systems: Annex 11.
  • Use concepts and guidance of ICH Q8, Q9, Q10 and Q11.
  • Apply a quality risk management approach throughout the lifecycle
  • Determine the 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 manufacturer’s own programmes
  • May be used
  • Justify this approach
  • Adequate assurance that controls were in place throughout the acquisition of such data.

Organising and Planning

  • 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 the qualification/validation system

Include or reference information on at least the following:

  • Qualification and Validation policy
  • Organizational structure
  • Roles and responsibilities for qualification and validation activities.
  • Summary of the facilities, equipment, systems, and 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 a quality risk management approach
  • Repeat Risk assessment with increased knowledge & Changes
  • Project Phase
  • Commercial Phase
  • Document how 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 authorized by appropriate personnel as defined in the pharmaceutical quality system.
  • Define the inter-relationship between documents in complex validation projects
  • Prepare validation protocols that define the critical systems, attributes, and parameters and the associated acceptance criteria.
  • Documents may be combined, 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 the next stage
  • The release should be authorized by relevant responsible personnel
  • Release may be a part of the validation report or as a separate summary document
  • Conditional approval to proceed to the next qualification stage is 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 the End of use of the equipment, facility, utility, or system.

The main stages and some suggested criteria that 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 by the vendor before delivery.
  • Confirm compliance with URS/functional specification before 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 an 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, pipework 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 behavior
  • 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.


Evaluate at an appropriate frequency to confirm that the 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.
  • A robust product development process is 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 is 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 program before 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 program

Site Transfer

  • Transferred from one site to another
  • Within the same site
  • Several 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

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

Attributes and parameters

  • Important to ensure 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 the criticality of parameters & attributes.

Process validation batches

  • Same size as the intended commercial scale batches
  • Justify the 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,
  • Otherwise, justify

General Principles

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

Design Space & Mathematical Models

  • Could be used for Process control strategy

The 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 authorization
  • Clinical trial authorization.

Investigational medicinal products (IMP),

  • Refer to Annex 13.

Concurrent validation

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

Traditional process validation

  • A 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 products.

Generally acceptable

  • Without prejudice to the earlier requirement
  • A minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process.
  • An 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 ongoing 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 is 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 to traditional process validation for
  • Products developed by a quality-by-design approach
  • Scientifically established control strategy during development
  • A strategy that 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 products.
  • 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 that 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 the 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

The above should be transported as defined in the

  • Marketing authorization
  • 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 that 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 a 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 – This 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 the 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 procedures for all product contact equipment.
  • Simulating agents may be used with appropriate scientific justification.
  • Similar types of equipment may be grouped together
  • Justify 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.
  • The 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
  • Assess all cleaning processes
  • Determine variable factors that 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 definition 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 on 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


  • Swabbing
  • Rinsing
  • Other means depending on the production equipment.
  • Sampling materials and methods 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 to prove that the cleaning method is validated

Cleaning process

  • Ineffective
  • Not appropriate for some equipment


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

Manual cleaning of equipment

  • Confirm the effectiveness of the manual process at a justified frequency.

Change Control

 Control of change

  •  An 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, and Assess the 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.


  • Authorized
  • Approved
  • Responsible persons
  • Relevant functional personnel
  • Follow the pharmaceutical quality system.
  • Review supporting data
  • Confirm impact of change has been demonstrated before final approval.
  • Evaluate the effectiveness of change
  • Confirm that the change has been successful
References: New EU Requirements for Qualification & Validation by GMP EDUCATION: Not-for-Profit Organization

About Pharmaceutical Guidanace

Ms. Abha Maurya is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 18 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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