HandOuts General update and requirements of Annex 15 … · General update and requirements of Annex 15 ... • Significate changes and/or deviations to approved protocol during

2016-05-26

1

General update and requirements of Annex 15

“Qualification and Validation”ISPE NORDIC CONFERENCE

STOCKHOLM, SWEDEN26th MAY 2016

Inger JönebringSenior GMP Consultant

ISPE Nordic 2016-05-26 2

Why has Annex 15 been updated?


• The previous version of Annex 15 was published in September 2001 and unmodern since there has been significant changes in the GMP environment and advancements in manufacturing technology and continuous manufacture processes

2016-05-26

2

Changes/Updates in Annex 15


• Principles of ICH Q8, Q9, Q10 and Q11 has been included• Cross-reference made to Annex 11 Computerised systems • More details in the section of Planning and documentation for

Qualification and Validation • Added information on the qualification stages for equipment,

facilities, utilities and systems• Major revision of the sections for Process and Cleaning Validation

New sections in Annex 15


• Ongoing Process Verification during Lifecycle • Verification of Transportation • Validation of Packaging • Qualification of Utilities • Validation of Test Methods

Organising and Planning for Qualification and Validation (update section)• Qualification and validation activities should be planned and take the

lifecycle of facilities, equipment, utilities, processes into consideration.

• Qualification and validation should be performed by suitably trained personnel.

• Personnel who works with validation should report as defined in the Pharmaceutical Quality System. Not necessary report to Quality Assurance function.

• Appropriate quality oversight over the validation life cycle.


2016-05-26

3

Organising and Planning for Qualification and Validation (update section)• The section on VMP extended with:

• Organisational structure including roles and responsibilities• Change control and deviation management• Guidance on developing acceptance criteria• Qualification and validation strategy, including requalification (if applicable)

• Quality Risk Management approach should be used for qualification and validation activities.

• Appropriate checks should be incorporated into qualification and validation to ensure obtained data integrity.


Documentation (update section)

• Good Documentation Practices are important to support knowledge management throughout the product lifecycle.

• Documentation should be approved by appropriate personnel defined in Pharmaceutical Quality System

• Validation protocols should define the critical systems, attributes and parameters and associated acceptance criteria

• Documents can be combined together e.g IQ and OQ• When third party supply the validation services personnel at the

manufacturing site should confirm suitability and compliance with internal procedures before approval.


Documentation (update section)

• Significate changes and/or deviations to approved protocol during execution e.g. acceptance criteria, operating parameters should be documented as a deviation and be scientifically justified.

• The text regarding formal release for the next stage has been extended with information that it could be as part of the validation report or separate document.

• Conditional approval for next step if certain acceptance criteria or deviations have been fully addressed and documented that there is no significant impact on next activity.


2016-05-26

4

Qualification stages for equipment, facilities, utilities and systems


User Requirement Specification (new section)


• The specification for equipment, facilities, utilities or systems should be defined in a URS and/or functional specification.

• The URS should be written with quality elements in mind, as well as minimising GMP risks and should be a point of reference throughout the validation life cycle

Design qualification (updated)


• Next step of qualification of equipment, facilities, utilities or systems where the compliance of the design with GMP should be demonstrated and documented.

• The requirement in the URS should be verified during Design Qualification

2016-05-26

5

Factory Acceptance Testing/Site Acceptance Testing (new section)


• The URS and DQ sections refers to “equipment, facilities, utilities and systems” but only equipment is mentioned for FAT/SAT.

• Before delivery and installation on site the equipment should be confirmed to comply with the URS/FS at the vendor.

• Testing and documentation reviews carried out during the FAT may need to be repeated once delivered on site at SAT or IQ/OQ

• FAT may be supplemented by the execution of SAT.

Installation Qualification


• More or less the same as in the previous version.

Operational Qualification• New in this version: OQ normally follows IQ but depending on the

complexity it may be performed as a combined Installation/Operation Qualification (IOQ).

• The new version no longer states that the completion of a successful OQ permits a the formal release of the product

Performance Qualification


• New in this version: PQ normally follows IQ and OQ. However it may in same cases be appropriate to performed in conjunction with OQ or Process Validation.

• The PQ should cover the process operating range.• There is also potential confusion using the abbreviation “PQ” within

industry as the US FDA Process Validation Guide defines PQ as “Process Qualification”

2016-05-26

6

Re-Qualification (Re-Validation in previous version)


• Facilities, utilities, systems should be evaluated at appropriate frequency to confirm that they remain in a state of control.

Process Validation


• The requirement and principles outlined in this section are still applicable to the manufacture of all pharmaceutical dosage forms, and now also cover site transfer and ongoing process verification.

• Only prospective and concurrent validation is considered accepted.Retrospective validation no longer acceptable

• Process validation requires a robust process development process to succeed.

• The process development can be in a traditional approach or a continuous verification approach.

Process Validation


• Process Validation of new products shall cover all intended strengths and site of manufacturing

• Process Validation due to site transfer can number of batches be reduced by bracketing

• Process Validation should establish if Process Parameters and Quality Attributes are considered important to ensure validate status and acceptable product quality.

• Critical or non-critical Process Parameters and Quality Attributes should be identified.

• If validation batches are released to market this should be pre-defined. These batches should fully comply with GMP, validation acceptance criteria and marketing authorisation.

2016-05-26

7

Process Validation –Concurrent validation


• Concurrent validation can be used in exceptional circumstances where there are strong benefits for the patient to start regular production before validation is completed.

• Concurrent validation shall be documented in the VMP.• Sufficient data shall support a conclusion that the batch meets

acceptance criteria. The result and conclusion shall be documented and available for Qualified Person prior certification of the batch.

Process Validation –Traditional Process Validation


• Number of batches and samples should be based on Quality Risk Management principles

• Generally minimum of three (3) consecutive batches under routine conditions

• An initial Process Validation with three batches may need to be supplemented with further batches from an ongoing process verification

Process Validation –Continuous Process Verification


• Continuous Process Verification (CPV) can be used when the Product developed has been done with a Quality by Design approach

• Process Analytical Technology and Multivariate Statistical Process may be used as tools.

• General principles of Process Validation shall be applied

Hybrid Approach• Mix of Traditional Process Validation and Continuous Process Verification

2016-05-26

8

Process Validation – Ongoing Process Verification during Lifecycle


• The glossary says that Ongoing Process Verification is known as Continued Process Verification which might lead to confusion.

• Monitoring product quality to ensure that the state of control is maintained throughout product lifecycle

• Statistical tools could be used to support any conclusion to ensure state of control

• Ongoing Process Verification should be used during the product lifecycle to support validation status of the product in the Product Quality Review.

Verification of Transportation (new section)


• Verification of transportation ensures product(s) and samples are transported in accordance with conditions defined in the Marketing Authorisation and/or product specification file.

• Seasonal variations should also be included in the validation.

Validation of Packaging (new section)


• Packaging should be validated as variation in equipment processing parameters during primary packaging may have impact on the product i.e. blister strips, sachets etc.

• Equipment used for primary packaging shall be qualified with defined critical process parameters e.g. temperature, machine speed, sealing pressure (both minimum and maximum operating range)

2016-05-26

9

Qualification of Utilities (new section)


• The quality of steam, water, air, other gases etc should be confirmed following installation using the qualification steps described in previous section.

• Extend qualification should reflect any seasonal variations and intended use.

Validation of Test Methods (new section)


• All analytical method used in validation should be validated• Refer to Chapter 6 ”Quality Control” of the Eudralex• Validation of microbiological method shall include confirmation that

product not interfere the recovery of microorganisms• Validation of microbiological method for testing of surfaces shall

include confirmation that sanitising agent do not influence the recovery of microorganisms

Cleaning Validation (updated section)


• Visual clean is an important part of cleaning validation but not the accepted as the only acceptance criteria.

• Limits for the carry-over of product residues shall be evaluated from a toxicological perspective.

• No longer acceptable to have three consecutive batches to demonstrate that the cleaning process is validated. A risk assessment shall justify the number required.

• Worst case product approach shall consider toxicity, PDE aswell as solubility

• Since cleaning validation can take some time cleaningverification might be needed.

2016-05-26

10

Change Control (updated section)


• The control of change is important part of knowledge management and should be handled within Pharmaceutical Quality System

• Where design space is used, the impact on change to the design space should be considered against the registered design space and the need for any regulatory assessed.

• Evaluation of the change shall be used to determine the potential impact on e.g. product quality, documentation, validation or regulatory status and plan for e.g. process validation

• Once the change has been executed an evaluation of its effectiveness should be carried out to confirm that the change has been successful


Thank you for your attention!

Inger Jö[email protected]

+46 70 333 30 50