New Zealand Healthcare Pharmacists' Association Compounding Nutrition & Oncology SIG
New Zealand Healthcare Pharmacists' Association Compounding Nutrition & Oncology SIG
New Zealand Healthcare Pharmacists' Association Compounding Nutrition & Oncology SIG
15.0 TRAINING______________________________________________________________28
General Notes
The key elements of a qualification and validation program should be clearly defined and
documented in a Validation Master Plan. The process should establish and provide documentary
evidence that: premises, supporting utilities, equipment and processes have been designed in
accordance with the requirements of GMP. This normally constitutes the Design Qualification or
‘DQ’ and includes confirmation that the premises, supporting utilities and equipment have been
built and installed in compliance with their design specifications (this constitutes Installation
Qualification or ‘IQ’) and that they operate in accordance with their design specifications (this
constitutes Operational Qualification or OQ).
A specific process will consistently produce a product meeting its predetermined specifications and
quality attributes (this constitutes Process Validation or PV. The term Performance Qualification or
PQ may be used also).
Purpose
The VMP is intended to be a ‘live’ document that supports the design and construction of any
production facility, its subsequent operation, maintenance and changes to the facility for its life
span. The VMP should present an overview of the entire validation operation, its organisational
structure, its content and planning. The core of the VMP is the list/inventory of items to be validated
and the planning schedule.
The VMP should provide your organisation with the basis for validation and quality system
activities required for cGMP compliance. This will enable any sterile or non-sterile medicinal
product that is produced, processed, stored or distributed, by the manufacturing unit, to be
validated under the control of an appropriate quality system.
The VMP should provide a cross-reference to other documents, such as SOP’s, validation
protocols, validation reports, and design plans. A rationale for the inclusion or exclusion of
validations, from the approach adopted should be included.
VMP Document
The VMP template is attached for completion as appropriate the document should be cross-
referenced with design specifications, design plans and other relevant documentation. Appendices
should contain all the relevant documentation referenced or stated in the VMP.
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Senior Engineer
Compiled by
Title: Name: Signature: Date:
Validation Engineer
APPENDICES
Draft 2 __/__/__
Draft 3 __/__/__
Revision 01 __/__/__
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Author: VALIDATION MASTER PLAN
Date: Revision 01
This Validation Master Plan has been compiled by a Validation Steering Committee (VSC) who
will also manage its execution. The members of the VSC are listed below and by their signatures
acknowledge their responsibilities to ensure that all validation activities are carried out as
described in this Validation Master Plan (VMP) and its annexes.
It is recommended that the members of the VSC should include, but is not limited to the following
areas of responsibility and expertise:
Pharmacy Production Team Leader
Pharmacy Senior Production Technician
Trust Senior Engineer
Pharmacy Quality Control Officer
cGMP Consultant
Validation Specialist
Additional members co-opted onto the VSC shall also sign below before undertaking any activities
associated with this VMP.
3.2 Responsibilities
With respect to the activities outlined in this VMP and its Annexes, including cleaning,
manufacturing practices and analytical methods, the responsibilities of key VSC members are
outlined below. Their responsibilities with respect to the overall operation are included where this
may have an impact upon validation activities.
Approval of new or amended documentation should be accomplished with the minimum of delay,
ideally within 2 working days, to facilitate the efficient operation of the facility
4.0 INTRODUCTION
6.1 Introduction
The pharmacy produces and issues a large number of products to in-patients,, out-patients and
other group hospitals/clinics.
This VMP applies to all production processes in the pharmacy.
6.3 Processes
For each product group, the manufacturing processes and the specific equipment utilised will be
described in detail. Specifically, these will include all processes critical to product quality.
Processes that involve ‘standard’ operation of equipment, e.g. weighing of product materials, may
be simply listed and referenced to appropriate equipment SOPs.
All rooms classified GMP grade D. Please refer to schedule of room data sheets located in
Appendix C. Served by HVAC zone 1. Please refer to drawing no. _____________.
Processes undertaken in this area include:
Non-sterile manufacture of creams, ointments, suppositories, oral suspensions, oral
liquids and capsules.
Extemporaneous preparation of creams, ointments and oral suspensions
Please refer to process flow diagrams located in Appendix A.
The zone is divided into 3 discrete areas and accessed by dedicated personnel change airlock
number _______.:
Hazardous non-sterile product manufacture, including Dithranol/Coal Tar, flammables
and cytotoxics.
Prep 1, 2 and 3. Non-sterile product manufacture (non-hazardous).
Equipment and bottle wash area. Pass boxes provide access for materials to local
storage areas within preparation areas.
Please refer to typical personnel, material, product and waste flow diagrams located in Appendix
A.
Rooms classified EU grades B, C and D served by HVAC zone 2. Additionally there is a small
equipment store. Please refer to schedule of room data sheets located in Appendix C, and to
drawing no. _____________.
Processes undertaken in this area include:
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An approved document translating the URS into a specification detailing how the requirements are
to be achieved. Together with the URS, this will provide the objectives and acceptance criteria for
the subsequent validation protocols.
The criticality of systems, equipment and components with respect to product quality will be
assessed using appropriate tools such as Impact Assessment (as described in the ISPE
Baseline Guide, Commissioning and Qualification).
Appropriately qualified personnel will conduct the assessments. The results will be formally
recorded and approved and will be used to provide information for the generation of appropriate
validation protocols and qualification tests within the validation protocols.
Subsequent activities e.g. cGMP Review will focus on the systems and equipment defined as
critical and having a direct impact on product quality.
A review of the developed designs will be performed for critical or bespoke items to ensure:
Compliance with the User’s Requirement
Compliance of design details with cGMP requirements
Practical validation tests will be possible
The findings of the Design Reviews will be recorded in written reports, which will be included in the
validation report, together with a record of any follow-up actions.
Some items of new or refurbished equipment may be subject to acceptance tests at the supplier's
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Date: Revision 01
premises. The data gained may be referenced in subsequent validation documentation provided
that:
These tests are pre-approved by the VSC
Witnessed by the VSC or their agents
Critical instruments are calibrated to appropriate standards
The equipment is not dismantled for transport to site
The manufacturer can certify that no subsequent changes have been made to the
construction or control systems. Summary reports of the Factory Acceptance Tests and
any follow up actions will be included in the validation documentation.
9.1.6 Commissioning
Relevant items will be fully commissioned prior to Installation Qualification. This is to ensure as a
minimum:
That all items of equipment, utilities and processes are safe to validate.
All mechanical assembly and pre-qualification checks have been completed.
Items of equipment, utilities and processes have been operated and shown to be fully
functional.
Documentation is completed and provided.
Commissioning records may form part of the qualification data to support the validation study
provided that they are traceable and have been audited by appropriate members of the VSC and
prepared by appropriately qualified personnel nominated by the VSC.
Installation Qualification (IQ) of items will be carried out to ensure that as a minimum:
The installation has been carried out according to specification and design intentions.
A record of the principal features of the item and its components as installed is available.
There is sufficient information available to enable the item to be operated and maintained
safely, effectively and consistently.
Each protocol will contain a rationale stating the validation requirements for the item of
equipment/system and will challenge items such as: materials of construction, lubrication, spare
parts, change parts, calibration, operations and maintenance manuals, training and standard
operating procedures.
If specified, the item or system shall be subjected to a Factory Acceptance Test (FAT) at the
vendors works before executing of IQ.
9.1.8 Calibration
All instruments deemed critical for product quality or safety must be calibrated according to
approved Standard Operating Procedures before commencing Operational Qualification of that
item. Generally this will be verified at IQ stage.
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Operational Qualification (OQ) test methodology will encompass testing, as close as possible to
production conditions, and where practical, “worst case” conditions.
The Operational Qualification will be carried out to determine as a minimum that:
All critical instruments have been calibrated to allow subsequent validation work to be
performed safely and with repeatable results.
The facility environments can be controlled in accordance with their specification.
Each item of process equipment operates as specified throughout its anticipated
operating range.
Each utility operates reliably as specified.
Each protocol will contain a rationale stating the validation requirements and methodology for the
item of equipment/system. The protocol will use commissioning documentation wherever possible
to prove the equipment/system meets the criteria set out for it. At this stage it will also be ensured
that draft standard operating and maintenance SOPs and training programmes identified in the
installation qualification documents are in place.
If specified, the item or system shall be subjected to a Site Acceptance Test (SAT) before
executing of OQ. Verified results from the SAT may be used to complete OQ tests where
appropriate.
Before setting the item or system in motion, the following will be necessary:
The required SOPs (usually manufacturer’s operating instructions) necessary for the safe
operation of the item or system will have been identified.
Site pressure testing will have been completed and documented.
Correct personal protection equipment and training in its use will have been provided.
HS&E risk assessments and method statements will have been completed where
appropriate.
Standard Operating Procedures (SOPs) must be in place to enable the items and systems to be
operated consistently as intended during Performance Qualification testing. These may include,
but are not limited to:
Operation
Cleaning
Testing
Sampling
Maintenance
Calibration
Production processes
QA/QC/Monitoring
Training
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Date: Revision 01
Performance Qualification (PQ) test methodology will encompass testing as close as possible to
production conditions, and where practical, “worst case” conditions.
Performance Qualification will determine whether the items, either in isolation or in combination
with other items, can process defined standard loads or batches of a representative product,
placebo, components or packaging consistently and repeatably to specification when operated
according to approved procedures and under normal production conditions.
In the case of items which are of simple construction and have few functions, Installation
Qualification checks and Operational Qualification tests (I/OQ) may be described in combined
Installation and Operational Qualification protocols. Similarly, Operational Qualification tests and
Performance Qualification (O/PQ) tests may be described in combined protocols.
The resulting protocols may be as brief as is necessary to adequately verify all aspects that impact
upon product quality.
Examples of equipment for which I/OQ may be appropriate are simple mobile vessels, balances,
suppository moulds, measuring glassware, etc.
Examples of equipment for which O/PQ might be appropriate are fridges, mixers, cooling coil, etc.
The purpose of process validation is to provide documented evidence that the process and facility
can consistently produce product that will satisfy a predetermined quality standard and comply
with the relative Regulatory Standards and, if applicable, meet or exceed previous recorded
quality levels.
PV requires three consecutive product batches to meet all acceptance criteria for in-process and
product testing and will involve enhanced sampling and testing using validated methods.
Any changes to equipment and/or systems critical to product quality will require PV to be
repeated.
New products/processes will be subject to PV.
Cleaning validation, which will be controlled through a separate validation plan (please refer to
Annex 1 of this document), will provide documented evidence that a cleaning procedure is
effective in reducing, to pre-defined maximum allowable limits, all chemical and microbiological
contamination from an item of equipment or a manufacturing area following processing. The
means of evaluating the effectiveness of cleaning will involve sampling cleaned and sanitised
surfaces and verifying the absence of product residues, cleaning residues and bacterial
contamination.
The installation and mechanical functionality of cleaning equipment and clean in place (CIP)
systems will be covered by equipment IQ and OQ protocols. The term cleaning validation is to be
used to describe the analytical investigation and subsequent verification of a cleaning procedure
or cycle. The cleaning validation protocols should reference background documentation relating
to the rationale for “worst case” testing, where this is proposed. It should also explain the
development of the acceptance criteria, including chemical and microbial specifications, limits of
detection and the selection of sampling methods.
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Particular note will be taken of the requirements of section 3.6 of the “Rules and Guidance for
Pharmaceutical Manufacturers and Distributors, 2002”, where potent or sensitising products such
as penicillins or cephalosporins are to be processed.
Analytical method validation and the associated laboratory equipment qualification, which will be
the subject of a separate validation plan, (please refer to Annex 2 of this document), provide
documented evidence that test methods are effective, reproducible and repeatable. The validation
protocols should reference background documentation relating to the rationale for the
determination of limits of detection and method sensitivity.
Validation of the analytical methods will be a pre-requisite for any analytical testing associated
with, for example, QC checks and cleaning validation assessments. It should be demonstrated
that the laboratory activities meet the requirements of GLP.
It is recognised that there is a very diverse requirement for storage and distribution due to:
The large number of products.
The limited shelf life of some products.
The temperature sensitivity of some products.
The requirement to manufacture ‘on demand’ to meet specific patients’ needs.
The economic need to produce maximum batch size wherever possible.
The storage and distribution processes will be controlled by appropriate SOPs and validated
where necessary. Appropriate RAs will be conducted to focus the validation activity upon those
products that are particularly susceptible to environmental conditions during storage and
distribution and have limited shelf life. The validation protocol(s) will be designed to verify that the
product(s) are maintained at specified environmental conditions during storage and during
distribution to the patient.
The point at which the responsibility for the product passes from the Pharmacy to intermediate
agents or the end user should be clearly defined. It will be verified that products are only delivered
to recognised persons or organisations who have the appropriate facilities and understanding to
maintain product quality.
A significant number of existing equipment items will be transferred to the new facility from other
pharmacies. All aspects of the relocation will be effectively managed and controlled by means of
an equipment re-location procedure. The procedure will, as a minimum, control all aspects of the
re-location that may impact upon cGMP. The procedure will include a model document that can
be adapted to suit all types of equipment. It should be completed in sufficient detail to ensure that
any required retrospective validation can be completed successfully.
The evidence of validation and associated documentation that exists for relocated equipment
should be reviewed and the scope of the validation exercise subsequently defined.
The relocated equipment will be subject to the IA procedure as defined in section 9.1.3. Where
the equipment is deemed to be of direct impact, then it will be subject to the same qualification
process as new items. However, it is recognised that the quantity and/or quality of the supporting
documentation may be limited. In such cases, the criticality of components should be taken into
consideration and steps taken to establish documented evidence that cGMP requirements are
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satisfied. The methodology used should be described in the rationale section of the respective
qualification protocols.
Typical activities may include:
Non-destructive testing to establish nature of product contact materials.
Review of process and batch data to provide appropriate OQ and PQ acceptance criteria.
Modification of existing SOPs to reflect use of the equipment in the new facility, with
subsequent testing using the modified SOPs.
Review of maintenance records to establish planned maintenance programme.
Re-calibration of critical instruments.
Annotated digital photography of equipment to provide pictorial evidence of component
layout and identification.
Tagging of components.
Review of training records to establish re-training requirements.
A copy of the equipment re-location procedure and model document will be placed in Appendix B.
Only to be included if any items of equipment have a programmable logic controller (plc).
It is a requirement of cGMP that effective preventative maintenance procedures are in place and
are followed correctly.
The validation activities will ensure that these procedures are developed and approved. The
procedures will apply to all equipment and systems that may have a direct or indirect impact upon
product quality.
Maintenance activities will be scheduled such that the minimum requirements for maintenance are
met and will be integrated with production activities.
Only approved methods and materials will be used during maintenance activities.
A schedule of all maintenance procedures shall be prepared and maintained to support the facility
during its life cycle. Appropriate procedures will be cross-referenced in the validation protocols
A list of all maintenance procedures will be indexed or referenced in Appendix B.
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15.0 TRAINING
Procedures for the training of personnel will be established. These procedures will ensure that:
The appropriate level of training and education is provided for all personnel employed
within the facility.
Training records are established and maintained for all personnel employed within the
facility.
The training will be referenced to all the SOPs identified or referenced in Appendix B.
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Appendix A
CONTENTS SECTION
Product List
Appendix B
CONTENTS SECTION
Equipment List
Validation Matrix
Appendix C
CONTENTS SECTION
Drawing Schedule
Drawings
Appendix D
CONTENTS SECTION