White Paper: EU GMP Guide-Annex 15 Qualification & Validation Draft Released

White paper:
EU GMP Guide-Annex 15
Qualification & Validation draft
released
In February 2014, a draft of the revised Annex 15 was

released by the European Commission (EC) for
public comment. The draft version is based on an
EMA Concept Paper, published in November 2012
which outlined various reasons for the revision of Annex 15.
This document was prepared in February 2016, any content including links and quoted regulation may be out of date. Please refer to the
appropriate source for the most recent information. We endeavour to keep an up-to-date record of information at www.pharmout.net.
2016 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited.
MKT_TMP200_01_r06
PharmOut white paper:
EU GMP Guide-Annex 15 Qualification & Validation draft released
Introduction:
The current version of Annex 15 of the EU Guide to GMP was originally published in September
2001, and since then there have been significant changes in the GMP environment. The EMA is
in the process of updating its guideline on Process Validation (a draft version is currently
available), and there have been advancements in manufacturing technology and continuous
manufacture processes. There has also been many changes to other Chapters and Annexes in
the EU GMP guide, which have an impact on Annex 15, and therefore the revision of this Annex
is required. Also the current version of the US FDA Guide on Process Validation, as well as the
approaches in ASTM E2500-07 Standard Guide for Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment may have also
justified the change.
Who is affected by the changes?

Manufacturers may be directly affected by the changes if they sell the following categories of
products into EMA regulated markets once the Annex is revised and effective:
Human drugs
Veterinary drugs
Biological and biotechnology products
Active pharmaceutical ingredient (API) manufacturers
Medical devices manufacturers are not directly affected; however, the guidance may contain
useful information for qualification and validation activities.
Manufacturers in other non-EU PIC/S regulated markets are likely to be affected indirectly. The
close alignment of EU and PIC/S means that PIC/S may adopt the guidance in full, or develop its
own guidance based on the EU document.
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Page 2 of 17 MKT_TMP200_01_r06
What are the key changes in the new guidance?

The key change in the draft is the inclusion of the principles of ICH Q8, Q9, Q10 and Q11 (see
Figure 1 below). These principles allow the use of concepts such as knowledge management
(ICH Q8 & Q10) and science and risk-based approaches (ICH Q9) to support lifecycle validation &
qualification activities, and the use of a design space (ICH Q8) for Process Validation.
Figure 1: ICH Q8, Q9, Q10 & Q11.
Other major changes within the draft are detailed in the list below, some of which will be
discussed in greater detail later:
Cross-reference made to Annex 11 Computerised systems
Planning and documentation for Qualification and Validation
Added information on the qualification stages for equipment, facilities and utilities
Major revision of the Process and Cleaning Validation and sections
New sections added on:
o Ongoing Process Verification during Lifecycle
o Verification of Transportation
o Validation of Packaging
o Qualification of Utilities
o Validation of Test Methods
Planning and documentation for Qualification & Validation

During the planning phase, it is now expected that all stages of the lifecycle for equipment,
facilities, systems and processes /products need to be taken into consideration. In terms of
organisation during qualification and validation, the draft indicates that the Pharmaceutical
Quality System (PQS) should define the Validation staff requirements (suitably trained to follow
procedures) and the responsibility for oversight over the whole validation lifecycle, in alignment
with Chapter 1 of the EU GMP Guide. The Annex indicates that this responsibility (including
validation document approval) may not necessarily be a quality management or quality
assurance function, but needs to be appropriate over the whole validation lifecycle. This shift
in appropriate oversight aligns with the thinking in ASTM E2500, which does not mention
responsibilities for someone within a quality function, but instead allows for Subject Matter
Experts (SMEs) to confirm acceptance of verification and release of the manufacturing
systems, authorising fitness for its intended use.
The draft still states that the Validation Master Plan (VMP) should define the key elements of the
validation program but now should also contain the "current validation status" of "facilities,
systems, equipment and processes" and also define the ongoing validation strategy, including
requalification/revalidation. It does not mention utilities, but may be assumed under "systems".
The VMP should now also cross-reference the template formats used for protocols and reports,
as well as assessment of resources required for the entire project. The VMP should also
summarise how acceptance criteria will be handled and provide clarity on deviation
management during validation. To align with the lifecycle approach, the VMP should confirm
that materials used for validation are of sufficient quality and obtained from appropriately
qualified suppliers.
Assessment of risk:
As part of the alignment with ICH Q9, a well-documented quality risk management approach
should be used to justify validation activities. As knowledge and understanding increases during
the project phase and during commercial manufacture, the risk assessments should be
repeated as required, with changes clearly documented and their impact understood.
Third Party Documents

The Documentation section of the draft outlines the importance of Good Documentation
Practice (GDP) for knowledge management throughout the validation lifecycle. For complex
projects, the inter-relationships between documents should be understood and visible and in
particular, when third party documents are used, they must be suitable and compliant with
company procedures before approval.
Handling Changes and Deviations

The instruction for the handling of protocols (pre and post execution) and reports has been
refined. Protocols should now also include definitions of "critical systems, attributes and
parameters which are important", along with their acceptance criteria. Section 2.6 states that
"Any changes to the approved protocol during execution should be documented as a deviation
and be scientifically justified." The Annex does not detail what types of "changes" could be
defined as a "deviations". For example, obvious typographical errors that have no impact on
protocol execution may require a change, but may not necessarily warrant a deviation. This
should be dependent on the manufacturers own PQS.
The Approval Process

The Annex also now clearly states that the qualification and/or validation report should
summarise the results obtained "against the acceptance criteria. Also, any subsequent changes
to the acceptance criteria should be scientifically justified with a final recommendation on
the outcome of the study detailed in the report. The formal release for the next step in the
validation process is still evident, and can be part of the approval of the validation report or
separate summary document authorised by the relevant responsible personnel. Section 2.9 now
also states that where "certain acceptance criteria or deviations have not been fully addressed",
with a documented assessment, "conditional approval" can be given to proceed to the next
validation stage, provided that there is "no significant impact" upon the next stage by doing so.
Qualification stages for equipment, facilities and utilities

As part of the alignment with ICH Q8 to Q11, the activities undertaken during qualification and
validation should "consider all stages from initial development of the user requirements
specification or initial process development through to the end of use of the equipment, facility
or process." This section goes on to suggest some of the stages and criteria that could be
used, but it may depend on the individual project circumstances and may be different. This may
allow for the implementation of other qualification and validation approaches such as ASTM
E2500. The suggested stages are summarised briefly below.
Figure 2: Possible qualification and validation stages from the Draft Annex 15.
User Requirements Specification (URS)

This section is new to Annex 15 and states that "the specification for new facilities, systems or
equipment should be defined in a URS and/or a functional specification" and is shown by point
(a) in Figure 2 above. This is a significant change as the current version of Annex 15 does not
mention a specification phase. 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". It does not state that a URS should be written for the process itself, and there is no
reference to the benefits/use of other types of specifications generally used within the industry.
Design qualification (DQ)

The current version of Annex 15 indicates that Design Qualification (DQ) could be the first
element for the validation of new facilities, systems or equipment. The draft version indicates
that the next element is DQ which serves to ensure the compliance of the design with GMP
and should be demonstrated and documented. It also states that the requirements of the
user requirements specification should also be verified during the design qualification, but
does not mention the Functional Specification, or indeed other specification such as design
specifications. This section could also have adopted a lifecycle approach to design qualification
preceding design reviews, with the same intent as described in ASTM E2500-07:
Design reviewsplanned and systematic reviews of specifications, design, and design
development and continuous improvement changes performed as appropriate throughout the
life-cycle of the manufacturing system. Design reviews evaluate deliverables against standards
and requirements, identify problems, and propose required corrective actions.
Factory acceptance testing (FAT) /Site acceptance testing (SAT)
The draft Annex now contains a new section on Factory Acceptance Testing (FAT) and Site
Acceptance Testing (SAT) of equipment only as shown in (b) in Figure 2 above. The URS and DQ
sections as above refers to facilities systems and equipment, but only equipment is mentioned
in this section. The section recommends the evaluation of equipment incorporating novel or
complex technology at the vendors site before delivery, and that equipment should be
demonstrated to be in compliance with the URS/functional specification, unless otherwise
justified. Testing and documentation reviews carried out during the FAT may not need to be
repeated once delivered on site if transport and installation has no impact. The appropriateness
of carrying out more testing or not should be assessed and documented.
Installation qualification (IQ)

The definitions and expectations of Installation Qualification (IQ) are the same in both versions
of Annex 15, but the new draft also states that the installation should be "as detailed in the
design and confirmation of current engineering regarding drawings and specifications" and the
IQ must include "verification of the correct installation against pre-defined criteria". This is an
obvious requirement for any protocol, but is not evident from the current version of Annex 15.
Operational qualification (OQ)

The OQ section in the draft now details that depending on the complexity of the equipment, a
combined IQ/OQ may be performed. It does not state that the same is true for facilities,
systems, utilities and/or processes. The draft no longer states that the completion of a
successful OQ permits the formal release of the facilities, systems and equipment, but it can
be inferred from point 2.9 of the draft that this approach is acceptable.
Performance qualification (PQ)

For Performance Qualification (PQ), the draft allows for the qualification activities to be
performed in conjunction with OQ or Process Validation. Section 3.14 now details what a PQ
"could" include instead of what it "should" include, as per the current version of Annex 15.
Sampling and testing used to confirm process control should encompass what has been
previously developed from knowledge of the process and the facilities, systems or equipment
and justified. The tests should cover the process operating range "unless documented evidence
from the development phases which confirm the operational ranges are available".
It is important to note that the definition of Performance Qualification is somewhat different
within the current PIC/S document PI 006-3 that covers recommendations on VMP, IQ and QO,
Non-sterile Process Validation and Cleaning Validation. It includes a definition for Process
Validation, but states that the term Performance Qualification or PQ may be used also. There
is also potential for confusion using the abbreviation PQ within industry as the US FDA
Process Validation Guidance defines PQ as Process Qualification which has two elements:. (1)
is the design of the facility and qualification of the equipment and utilities and (2) is the process
performance qualification (PPQ). which combines the actual facility, utilities, equipment (each
now qualified), and the trained personnel with the commercial manufacturing process, control
procedures, and components to produce commercial batches, and will confirm the process
design and demonstrate that the commercial manufacturing process performs as expected.
Process Validation
The requirements and principles outlined in this section are still applicable to the manufacture
of all pharmaceutical dosage forms, and now also cover site transfers and ongoing process
verification. The Annex should be used in conjunction with the EMA guideline on Process
Validation, (currently in draft) which provides direction on what is required for regulatory
submission and GMP requirements. A White Paper on the EMA Draft Guidance can be found on
the PharmOut website, and a summary of the main sections of the EMA PV Guide are shown in
Figure 3 below. Note that Retrospective Validation is not mentioned in the draft, nor is it
mentioned in the draft EMA PV Guide. It is assumed that all validation will be either prospective
or concurrent in exceptional circumstances.
Figure 3: Process Validation approaches from the Draft Annex 15.
The Draft of Annex 15 has sub-headings with descriptions on Concurrent Validation, the
Traditional Approach, Continuous Process Verification and Ongoing Process Verification. The
only information on the Hybrid Approach is in section 4.24 where it states that A hybrid
approach using the traditional approach and continuous process verification for different
production steps can also be used, and a definition is missing from the Glossary. Within the
draft, the terms Ongoing Process Verification and Continuous Process Verification are used
and are further described below. Both terms are described as being the same in the Glossary,
but this may lead to confusion.
Section 4.3 states that products may be developed using a traditional approach or a continuous
verification approach but again, does not mention the hybrid approach here. It goes on to say
that however irrespective of the approach used, processes must be shown to be robust and
ensure consistent product quality before any product is released to the market. Manufacturing
processes should undergo a prospective validation programme wherever possible prior to
marketing of the product.
A lifecycle approach is applied linking product and process

development, validation of the commercial manufacturing
process and maintenance of the process in a state of control
during commercial production
Process Validation should be based on documented critical process parameters (CPPs) and
critical quality attributes (CQAs) as a result of risk assessment activities as applicable. If a
design space justification is used, the process knowledge and statistics used to confirm a state
of control should be available. Validation batches (including continuous process verification)
that are released to the market should fully comply with GMP & Marketing Authorisation and
meet all validation acceptance criteria.
The draft also indicates that the number of validation batches could be reduced by the use of a
bracketing approach for products which are transferred to another/within site where sufficient
product knowledge exists, and if a continuous manufacturing process is used, the batch size for
Process Validation should be justified. The options for Process Validation are discussed briefly
below.
Concurrent validation
The draft Annex indicates that concurrent validation may be acceptable in exceptional
circumstances "where there is a strong risk benefit to the patient" but the decision must be
justified and documented in the VMP and approved by authorised personnel.
The current US FDA Process Validation Guidance document provides greater detail on the
potential benefits to concurrent validation. It indicates that concurrent release might be
appropriate for processes used infrequently for various reasons including limited demand
drugs, radiopharmaceuticals with short half-lives or drugs that are medically necessary and are
being manufactured in coordination with the Agency (US FDA) to alleviate a short supply.
Traditional approach to validation

The "traditional approach" allows the manufacturer to produce a number of batches under
routine conditions, confirming reproducibility. The number of batches pre- defined and the
sampling to be undertaken must be justified based on QRM principles to demonstrate "a high
level of assurance that the process is capable of consistently delivering quality product". The
section also goes on to say that a minimum of three batches may be justifiable, but the
validation exercise may be supplemented with data from "subsequent batches as part of an on-
going process verification exercise.
Continuous Process Verification

CPV can be used for products that have been developed by a quality by design approach as an
alternative to traditional process validation, as discussed above. CPV should be based on a
"science based control strategy for the required attributes for incoming materials, critical
quality attributes and critical process parameters to confirm product realisation". This should
also include regular evaluation of the control strategy and the use of statistical tools and
Process Analytical Technology (PAT) may be used. The number of batches used to justify that
the process is consistent and capable must be justified. CPV can also be used after changes or
during ongoing process verification even if the process was initially validated using the
traditional approach, but a substantial amount of product and process knowledge must have
been gained from experience and historical data first, and again justified.
A Hybrid Approach using the Traditional Approach and Continuous Process Verification
together for different production steps can also be used, but there is little detail on the
Traditional Approach here.
Ongoing Process Verification during Lifecycle

Ongoing process verification is required periodically to ensure that a state of control is
maintained throughout the product lifecycle. The period of the verification should be based on
the level of process understanding and process performance at all times during the product
lifecycle. This ongoing verification should be used to support the Product Quality Review and
should be conducted under an approved protocol with a report, using statistical tools to support
conclusions made. The report should contain a detailed assessment of the variability and
capability of the process and ensure a state of control. It should also assess changes during
the product lifecycle and their impact on the validated state of the process.
Cleaning validation
Within the Glossary of the draft, the definition for Cleaning Validation has changed from "will
provide equipment which is suitable for processing medicinal products" to "will remove all
traces of the previous product used in the equipment." This statement is weaker than the older
definition as it only infers that previous product be removed and not potential contamination
such as bioburden and endotoxin that might be present.
The draft identifies that visually clean is an important part of cleaning validation but not
acceptable acceptance criteria on its own. The Annex identifies that cleaning validation may
take some time to complete and that "ongoing verification" after each batch may be required for
a period of time to gather sufficient data.
Section 9.5 states that the "Limits for the carry-over of product residues should be based on a
toxicological evaluation to determine the product specific permitted daily exposure (PDE) value"
and should be documented in a risk assessment. This is not particularly helpful for non-toxic
products/administration routes.
The PDE represents a dose that is unlikely to cause an adverse effect if an individual is exposed
at this dose every day for a lifetime. This approach is not new and the PDE concept is already
used in the ICH Guideline Q3C (R4) Guideline for Residual Solvents. The PDE determination is
carried out substance-specific on the basis of all available toxicological and pharmacological
data from clinical, preclinical or toxicological studies by means of the NOEL (no-observed-
effect-level). The NOEL is the highest dose at which no critical effect is observed. This ties in
with EMAs draft guide titled Guideline on setting health based exposure limits for use in risk
identification in the manufacture of different medicinal products in shared facilities released in
December 2012. The acceptance criteria should also consider the "potential cumulative effect of
multiple equipment in the process equipment train". The assessment for potential microbial
and endotoxin contamination should also be assessed as applicable, along with the influence of
dirty and clean hold times for equipment.
Section 9.8 states that "where a worst case product approach is used as a cleaning validation
model, the rationale for selection of the worst case product should be justified and the impact of
new products to the site assessed" and "when there is no single worst case product when using
multi-purpose equipment, the choice of worst cases should consider toxicity and PDE value as
well as solubility. Worst case cleaning validation should be performed for each cleaning method
used".
Typically, the cleaning procedure should be performed an

appropriate number of times based on a risk assessment and
meet the acceptance criteria in order to prove that the cleaning
method is validated
The Annex no longer looks for three consecutive batches to demonstrate that the cleaning
process is validated. It now states that cleaning process be carried out an appropriate number
of times based on a risk assessment.
Cleaning verification may be used instead (but principles still based on the principles in the
Cleaning Validation section of the Annex) of cleaning validation when manufacturing batches
infrequently or for investigational medicinal products. If cleaning validation has been proven to
be ineffective/not appropriate for some equipment, then dedicated equipment should be used
for each product.
New Sections
Ongoing Process Verification during Lifecycle
This section has been discussed in the Process Validation section above.
Verification of Transportation
Verification of transportation ensures product(s) and samples are transported in accordance
with the conditions defined in the Marketing Authorisation, product specification file or by the
manufacturer. Seasonal variations should also be considered. The Annex states that a risk
assessment should be performed to consider the impact of conditions other than temperature
during transport and examples are given in this section.
Validation of Packaging
Packaging should be validated as variation in equipment processing parameters during primary
packaging may have an impact on the product i.e. blister strips, sachets etc.
Qualification should encompass the entire operating ranges defined for the critical component
parameters.
Qualification of Utilities
The quality of utilities such as water, steam, air, gases etc. should be confirmed following
installation. Extent of qualification should reflect seasonal variation and intended use. A risk
assessment should be carried out to mitigate any risks of failure and is particularly important
for direct product contact systems like Heating Ventilation Air Conditioning (HVAC) systems.
Validation of Test Methods

Analytical methods (including microbiological methods) used for qualification, validation or
cleaning should be appropriately validated. This section cross references Chapter 6 of the EU-
GMP guide Part I.
8.3 states that where microbial testing of surfaces in clean rooms is carried out, validation
should be performed on the test method to confirm that sanitising agents do not influence the
result.
Other notable changes within the Annex

Re-qualification
The "Re-validation" section has been retitled as "Re-qualification" and states that "Facilities,
utilities, systems, equipment should be evaluated at an appropriate frequency to confirm that
they remain in a state of control". Also, "Where additional requalification is necessary and
performed at a specific time period, the period should be justified and, the criteria for evaluation
defined. Furthermore the possibility of incremental changes should be assessed".
Change Control
11.3 of the draft states that "Where design space is used, the impact on changes to the design
space should be considered against the registered design space within the Marketing
Authorisation and the need for any regulatory actions assessed". QRM should be used to
evaluate planned changes and assess their impact and to "avoid unintended consequences and
to plan for any necessary process verification or requalification efforts". Once the change has
been executed, an evaluation of its effectiveness should be carried out to confirm that the
change has been successful.
Glossary
The glossary now contains descriptions of the following terms new to the draft:
Bracketing approach
Continuous process verification
Control Strategy
Critical process parameter (CPP)
Critical quality attribute (CQA)
Design Space
Knowledge Management
Lifecycle
Ongoing Process Verification (also known as continued process verification)
Product realisation
Quality by design
State of control
Traditional Approach
Conclusion
The draft guide has been brought in line with updates to ICH Q8-Q11 and the lifecycle approach,
as well as current trends in pharmaceutical manufacturing. There are a number of significant
changes in terms of how equipment, facilities and systems can be planned and qualified, and
how processes can be validated.
It is also no longer acceptable to have three consecutive batches to demonstrate that the
cleaning process is validated-a risk assessment is required to justify the number required.
Included is guidance on the Verification of Transportation as well as separate sections on
Validation of Packaging, Utilities and Test Methods.
The document is currently available for public consultation with the deadline for comments set
for May 2014. The draft is subject to change and it may need further clarity on a number of
sections as highlighted above to avoid confusion including CPV, ongoing process verification and
deviations. It is expected that the new version will be adopted be the European Commission in
October 2014.
References
Concept Paper on revision of Annex 15 of the GMP guide (EMA/INS/GMP/705397/2012),
European Medicines Agency, November 2012.
EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Annex 15 Qualification and
Validation, 2001.
ASTM E2500-7 Standard Guide for Specification, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems and Equipment, June 2007.
EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Annex 15 Qualification and
Validation, 2014 draft.
International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline, ICH Q8
Pharmaceutical Development, 2009.
Quality Risk Management, 2005.
Pharmaceutical Quality System, 2008.
Development and Manufacture of Drug Substances, 2012.
EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, EU Annex 11
Computerised Systems, 2011.
Guideline on Process Validation (draft), European Medicines Agency, 2012.
ASTM E2500-7 Standard Guide for Specification, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems and Equipment, June 2007.
PIC/S Recommendations on Validation Master Plan, Installation and Operational Qualification,
Non-sterile Process Validation and Cleaning Validation, PI 006-3, 2007
Sources
Links used within this document are prone to change. Please refer to the appropriate source for
the most recent information. We endeavour to keep an up-to-date record of information at
www.pharmout.net
PharmOut is an international GMP consultancy serving the Pharmaceutical, Medical Device and
Veterinary industries. PharmOut specialises in PIC/S, WHO, United States FDA, European EMA,
and Australian TGA GMP consulting, engineering, project management, training, validation,
continuous improvement and regulatory services.
Our team includes international GMP experts who have previously held leadership roles within
regulatory bodies.
For more information please visit www.pharmout.net or contact us at info@pharmout.net.

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White paper:

In February 2014, a draft of the revised Annex 15 was

Who is affected by the changes?

What are the key changes in the new guidance?

Figure 1: ICH Q8, Q9, Q10 & Q11.

Planning and documentation for Qualification & Validation

Third Party Documents

Handling Changes and Deviations

The Approval Process

Qualification stages for equipment, facilities and utilities

User Requirements Specification (URS)

Design qualification (DQ)

Installation qualification (IQ)

Operational qualification (OQ)

Performance qualification (PQ)

Figure 3: Process Validation approaches from the Draft Annex 15.

A lifecycle approach is applied linking product and process

Traditional approach to validation

Continuous Process Verification

Ongoing Process Verification during Lifecycle

Typically, the cleaning procedure should be performed an

Validation of Test Methods

Other notable changes within the Annex

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