Пересмотр Руководства по GMP EC – Приложение 15

On 30 March 2015, the European Commission published revised version of Annex 15: Qualification and Validation of the EU GMP Guide. The new annex will become effective on 1 October 2015.

Comparing to current version of the annex, extensive changes have been made in some areas. Particularly, it relates to Process Validation and Cleaning Validation. In addition, there are also some new chapters added.

Revised version of Annex 15 emphasises a need of application of a quality risk management approach throughout the lifecycle of a medicinal product.

It is very important to underline, that retrospective validation is no longer considered an acceptable approach.

Validation Master Plan (VMP)

The VMP or equivalent document should define the qualification/validation system and include or reference information on at least the following:

1. Qualification and Validation policy;
2. The organisational structure including roles and responsibilities for qualification and validation activities;
3. Summary of the facilities, equipment, systems, processes on site and the qualification and validation status;
4. Change control and deviation management for qualification and validation;
5. Guidance on developing acceptance criteria;
6. References to existing documents;
7. The qualification and validation strategy, including requalification, where applicable.

QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS

Qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility or system. The main stages are indicated below:

User requirements specification (URS)

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

Design qualification (DQ)

The next element in the qualification activities. The requirements of the user requirements specification should be verified during the design qualification.

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

Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, at the vendor prior to delivery. FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.

Installation qualification (IQ)

IQ should be performed on equipment, facilities, utilities, or systems.

Operational qualification (OQ)

OQ normally follows IQ but depending on the complexity of the equipment, it may be performed as a combined Installation/Operation Qualification (IOQ).

Performance qualification (PQ)

PQ should normally follow the successful completion of IQ and OQ. However, it may in some cases be appropriate to perform it in conjunction with OQ or Process Validation.

Chapter entitled RE-QUALIFICATION is new. It says that equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm that they remain in a state of control.

PROCESS VALIDATION

Generally, process validation of new products should cover all intended marketed strengths and sites of manufacture. Bracketing could be used for new products, if strongly justified. For process validation of products which are transferred from one site to another or within the same site, the number of validation batches could be reduced by the use of a bracketing approach. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified.

It is especially important that the underlying process knowledge for the design space justification (if used) and for development of any mathematical models (if used) to confirm a process control strategy should be available.

According to the new version of Annex 15, there are three approaches to process validation: traditional, continuous and hybrid.

Traditional process validation

The number of batches manufactured and the number of samples taken should be based on quality risk management principles. Each manufacturer must 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. It is still generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process.

A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge.

Continuous process verification

For products developed by a quality by design (QbD) approach, where it has been scientifically established during development that the established control strategy provides a high degree of assurance of product quality, then continuous process verification can be used as an alternative to traditional process validation.

Hybrid approach

A hybrid of the traditional approach and continuous process verification could be used where there is a substantial amount of product and process knowledge and understanding which has been gained from manufacturing experience and historical batch data.

Ongoing Process Verification during Lifecycle

Ongoing process verification is applicable to all three approaches to process validation mentioned above, i.e. traditional, continuous and hybrid, and it supports the validated status of the product as documented in the Product Quality Review.

Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated.

There are another four new chapters entitled:

• VERIFICATION OF TRANSPORTATION,
• VALIDATION OF PACKAGING,
• QUALIFICATION OF UTILITIES,
• VALIDATION OF TEST METHODS.

CLEANING VALIDATION

A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation but it is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.

Limits for the carryover of product residues should be based on a toxicological evaluation¹.

¹ See EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process.

CHANGE CONTROL

The control of change is an important part of knowledge management and should be handled within the pharmaceutical quality system. Revised Annex 15 requires an evaluation of the effectiveness of change to be carried out to confirm that the change has been successful.