NMMU NOTES

Note:
 We live in an extraordinary information age where with right key word search, plethora of insight is
available on any subject, validation included. Upfront expectations naive or not are that students will
have already undertaken overview reading and have a basic grasp of validation terminology, philosophy
and execution steps. I would be happy to answer on any raised issues but would not present on basic
information that is readily on hand to them.
 Given my job function as Sterile Support Manager to Aspen SVP plant, there is a bias to parenteral
manufacturing in this presentation
Scope*:

 Validation environment
 Validation execution - Limited to brief cover of practical approach principles - expectations are that students
will have undertaken overview reading and have a basic grasp of validation terminology, philosophy and
execution steps

 Brief validation history, current major shift taken by regulatory authorities on validation

 Interpretation and application of new expectations

*Note: Bias to parenteral manufacture

Expected Outcome in a nut shell

 Provision of insight as to how the validation function has progressed from stand
alone, at interval qualification activities to an integrated process critically reliant on
Process performance and Product quality monitoring systems for claiming success

1. Validation basics
2. Typical process scope for parenteral plant
3. Validation context to Industrial Pharmacist
4. Current major shift taken by regulatory authorities wrt process validation
5. FDA Process validation guide (PVG)overview
6. SVP status in relation to shift - Interpretation and application of new expectations:
7. Knowledge management
8. Key concluding statements

1. VALIDATION BASICS
Definition
There is no universal definition of the term validation, however most versions embody
the same concept. The most influential are as follows and help to clarify the role of
Validation within a pharmaceutical quality system:
Validation - "Establishing documented evidence, which provides a high degree of
assurance that a specific process will consistently produce a product meeting its
predetermined specifications and quality attributes."
“US FDA - Guideline on the General Principles of Process Validation.”
Universal validation objectives
 Aid in ensuring product safety and efficacy;
 Provide assurance of product sterility;
 Support GMP;
 Provide documented evidence of suitability and correct operation of
equipment/processes;
 Maximize the business benefits to be derived from the equipment/processes;
 Minimize business risk.
Caution here There is an inescapable regulatory dictate for validation but there
has been exploitation in this field by consultants, equipment suppliers selling their
services which has resulted in non value adding activities - documentation
loading processes. It is crucial that you maintain balanced GMP – Commercial
outlook here and hence the next section defining tenets and strategy
Aside note: Yes there are Guidelines out but they are not and cannot be
prescriptive in all areas -
Harmonization efforts by different countries-regulatory bodies processes are
happening but just look at the snail pace in the case of pharmacopeal
standardization. WHO initiated the process way back with their international
pharmacopeia but it never caught on and I don’t think in my career life time left
will I see EP – USP without their own departures

Facilities-Equipment Qualification; Base tenets – strategy elements

 Diversity of validation task is such that it dictates for multidisciplinary approach.
There is a need to maintain a core validation department, however, subject to task,
other personnel can be co-opted into validation activities as appropriate to
circumstance and in some cases. Equally some functions can also be delegated to
other production support/specialist units. Such task includes, but is not confined to;
User Requirement Specification (URS) development, Functional specification (FS)
approval, Factory Acceptance Testing (FAT), Equipment commissioning where
predominantly reliance will be made on Engineering and contracted support.
- What we do actively pursue here and make part of validation officers
performance assessment is securing of cross functional capabilities so that we can
best service our function.
The reality however is that while we have individuals with SME status in a number
of fields, diversity of task is just too wide for validation team alone.
Equally you dont want to unnecessarily inflate the validation team with specialist
persons who will not be full time employed either.
Ultimately from a business perspective you have to recognize that validation is an
indirect cost center that has to be optimally managed
 Whilst responsibility for the Good Engineering Practices (GEP) and commissioning
function resides in the engineering department, these activities are an integral part
of facility/utility/equipment/process installation and qualification, and as such,
Engineering can provide validation with complete documented record of
 commissioning activity undertaken. Crucial that necessary marriage takes place
here
● Where cost effective and expedient to validation implementation, securing of
supplier validation packages as part of equipment acquisition processes can be
pursued and is acceptable. Remember earlier cautioning against exploitation You
do not want to be paying for something that should be part of the supply process
anyway
● Wherever possible, formal FAT processes must be undertaken to inspect and test
systems or major system components before delivery to the site. This to promote
quicker and more efficient remedy of any failings, so as to minimize delays to the
project schedule, that might arise from only discovering problems later on-site.
Methodology, outcome and documentation of such testing must wherever possible
be incorporated into commissioning, Site Acceptance Testing (SAT), Installation
Qualification (IQ), Operational Qualification (OQ), and validation activities that
follow. Hard lesson that we still have not fully learnt and we still have had
instances of “trying to correct equipment design and operation through validation
activities – Not a unique problem even for Multinationals who have far greater
licence for resource and infrastructure
● Specific to highly specialized equipment, cognizance must be taken that whilst the
onus remains on the primary facility for ensuring correct up front specification
requirements, primary equipment expertise resides in the equipment manufacturer.
Accordingly direct involvement in, and contribution by the equipment supplier in
such case, is key to equipment qualification. Equipment suppliers will play an
integral role in the any validation program.
● In cases where equipment suppliers themselves have established DQ, IQ, OQ, and
PQ Protocols to recognized industry standard, then subject to scrutiny affirming that
all requirements are met, such protocols can be directly incorporated into facility
qualification processes. All this requires is controlled introduction
● Scope and extent of qualification and validation and the likely impact of changes
must be determined and managed on an impact and risk assessment basis. – See
ISPE principles
● Wherever possible, self-validating controls and system checks must be built into
manufacturing processes. Crucial aspect of continued process verification
expectations - Tuck this in the back of your minds for when we get to later
sections
● Equipment must be maintained and calibrated as appropriate, at regular intervals
such that, in combination with system controls and checks, correct results can be
assured. Same prior comments apply here
KEY MESSAGE: AVOID DUPLICATION, CONTAIN COSTS, ENSURE THAT IT IS VALUE
ADDING, MAINTAINTIN CHRONOLOGY IN EXECUTION (latter easier said than done)

● Embrace and will apply wherever practical the following 10 guiding principles of
Good Commissioning and Qualification practices as laid out by the ISPE Qualification
Task Team 03/95): Reinforcement of the above

Focus on that which affects product quality. Qualifying equipment to put approved
protocols on the shelf is not the end goal; qualifying processes should be the primary
focus. To achieve this, definition and control of a process-based User Requirement
Specification is an important function with quality impact. The primary quality and
regulatory focus should be to ensure critical process parameters, critical functions, and
critical design features that could affect product quality are defined and controlled.
Requirements. User requirements, based on the process (and not on equipment or
systems), are the key to acceptability. The PQ is generally where user requirements are
confirmed as being satisfied. Hence, IQ/OQ are subordinate in importance to the PQ.
Risk assessments, process development and experimental design are used to identify
critical features, functions, and critical process parameters. These become the basis
for qualification (IQ/OQ/PQ). Having a solid process understanding will foster
regulatory expectations for Quality by Design.
Only critical process parameters will be used as the basis on which to define the
formal“qualification information.” This should also include any physical design features
or control functions that could impact the ability to clean, sterilize, sanitize, or properly
manufacture the product, to the extent these activities impact product quality and
safety.
All activities must contribute value to the start-up and delivery of manufacturing
capacity. Don’t do anything just for the sake of regulatory compliance. Activities that
are simply a paperwork exercise, resulting in no impact to installation, operation, or
performance of systems, should be reduced or eliminated. Engineering judgment
should be used to determine how to inspect or test specific features and functions of
equipment and systems.
Risk-based asset delivery. Different types of equipment and systems (custom, off-the
shelf, simple, complex, etc.) require different levels of attention to ensure quality. An
approach to defining how much “good engineering practice” should be applied to a
given item, based on risk of problems, should be applied rather than “cook book” lists
of activities and documents. The GAMP categories use this approach for automation
systems, similar approaches for equipment and systems should be defined and
described.
Value-added documents. Documents serve a useful purpose of controlling activities,
they ensure completeness, and they serve as a record of what occurred. Only data
which serves a useful purpose should be collected. Acceptability of documents should
be based on technical merit; documents should not be “dressed up” to meet some
imagined regulatory expectation. The operations and maintenance groups
should determine the acceptability of turnover packages, for it is they who will
ultimately use them for on-going operations and maintenance.
Use of supplier documentation. Supplier’s standard inspection and test
documentation may be used with no need for other documents to be produced that
duplicate this information, provided that documentation clearly shows the items of
interest have been verified or tested in an appropriate manner. This is subject to the
supplier being of adequate quality.
Test planning. Defined tests should only be carried out once (at an agreed location and
by agreed parties, i.e. either by the supplier or by the manufacturing company, with
accountabilities agreed upfront), unless there is a clear justification for undertaking
further tests at a later stage of commissioning. Commissioning should be a
comprehensive activity, with IQ/OQ as an audit that commissioning verified the
quality-impacting items. PQ may involve additional testing. Some tests may occur at
different stages of development/ implementation and therefore appear to repeats.
Fostering innovation. Any program must remain flexible enough to apply sound and
qualified scientific and engineering judgment based on the situation at hand and not
be too prescriptive as to stifle innovation.

Standard V model application Provides for at glance overview of primary

qualification processes

(1) Planning Phase (3) Qualification Phase

Does the process perform reliably under routine operating conditions
Performance
User Qualification
Requirement Protocol
Specification Report
Input > ‘What is Raw Data
must do” Deviation

Does the equipment work correctly

Functional Specification Operation Qualification
Supplier-> “What it will do” Protocol
Report
Raw Data
Deviation

Design Specification
Supplier ->How it will do it” “Was it built correctly”
Installation Qualification
Protocol
Report
Raw Data
Impact Assessment Deviation Reoprt
Design Qualification
F.S. <-> URS Comparison
Preliminary Risk Assessment

(2) Installation Phase Factory Acceptance Installation Site Acceptance Test

Test
Underpinning requirements to such validation strategy is that commitment must
prevail for:

 Equipment acquisition to be confined to Industry established equipment

manufacturers for which known GEP repute can be determined;
 Use of high quality production components;
 Ensuring correct equipment maintenance practices;
 Ensuring correct personnel selection and training provision practices.
Without the above very easy for undermining of validation efforts

Validation Master Plan (VMP) - Key reference document that you need to be aware
is available to you definition
A Validation Master Plan is a high level document that establishes an umbrella
validation plan for the entire project and summarizes the manufacturer’s overall
philosophy and approach, to be used for establishing performance adequacy. It
provides information on the manufacturer’s validation work programme and defines
details of and time-scales for the validation work to be performed, including stating the
responsibilities relating to the plan. ( “World Health Organization – Supplementary
Guidelines for GMP Validation)

2. TYPICAL EQUIPMENT - PROCESS QUALIFICATION SCOPE FOR A PARENTERAL

PLANT
Scope and cover includes qualification of
 Utilities
 HVAC systems and controlled environments
 Production processing equipment
 Autoclaves – Moist heat sterilization process
 CIP/SIP systems
 Cleaning processes
 Dry heat sterilization-depyrogenation Oven – tunnel processes
 Irradiation sterilization
 Filtration sterilization
 Equipment - Product Hold times
 Media fill – Process simulation Unique to parenteral manufacture and subject
meriting separate discussion at high level
 Lyophilizers
 Isolators
 Manual & automated inspection systems
 Laboratory equipment
You should better understand the expectation for cross functional capabilities
within the validation department. Generally the case that validation
practitioners career development has been based on self taught - experiential
 basis over time but there are now master degrees like that offered by
Manchester University in Pharmaceutical engineering which very effectively
provide for validation qualification
3. VALIDATION CONTEXT TO INDUSTRIAL PHARMACIST
Discharge of professional – ethical obligations
 Validation service and support provides critical process insight and data to
pharmacists in day to day incurring of responsibility and decision making
processes
Advantages/benefits of involvement with or using validation as industry career
spring board
These include;
 With multidisciplinary demands of validation, exposure to resource, experience
and expertise unlike any other department - access to wealth of diverse
experience in accelerated time
 Privilege of working in a learning environment with intellectual/academic
stimulation – Irony within the production environment, is that pharmacists having
passed one of the most demanding degree courses, then find their focus devolved
down to very necessary but more mundane aspects of keeping the factory going –
not always intellectually challenging.
 Foothold in every area of the business including laboratory, production
engineering, QA
 Opportunity for individual growth, pursuit of specific areas of interest/expertise
 Opportunity to directly showcase to senior management individual capabilities
and expertise

Trying to sell the above as part requirement for making industry more attractive
career option for Pharmacists and so stemming the bleed and extraordinarily high
pharmacist turn over

 CURRENT MAJOR SHIFT TAKEN BY REGULATORY AUTHORITIES WRT PROCESS

VALIDATION –
TO WHAT EXTENT DID YESTERDAYS LECTURE COVER THIS TOPIC? REGARDLESS SO
CRITICAL THAT I WILL COVER IT AGAIN
4.
Key changes with the new approach to process validation
 progression from event/task execution to ongoing lifecycle review process
 Precipitates increased focus on process design with:
- heightened demands on Quality by Design(QBD) and Risk Assessment (RA) aspects
- Requirement for upfront better defining of the commercial manufacturing process
based on QBD & RA outcome as well as knowledge gained through tech transfer-
development - scale-up activities.
 Introduction of new terminology for process qualification – “Process Performance
Qualification” (PPQ), in lieu of process validation for process demonstration
 Formal imposing of continuous process verification requirements - This includes a
major paradigm shift from a product centric QMS approach to that of integrating
Technical, QA, QC, Validation, Production and Engineering departments and so
providing for more holistic approach in securing ongoing assurance of processes
remaining in state of control
 Responsibility for process validation no longer exclusively resides with
Technical/validation departments. “

5. FDA PROCESS VALIDATION GUIDE (PVG)OVERVIEW

Distillation of the PVG core elements/principles are:
 Structure on a lifecycle concept with objective of process validation being to
secure and demonstrate a state of ongoing control of process variability.
 Process validation not being an event or task that can be completed, rather
lifecycle of control across the entire product development and manufacturing
product lifetime.
 Three-stage model that begins with process design and ends only with the
discontinuation of manufacture;
- Stage 1 : Process design
- Stage 2 : Process Qualification – Old standard validation domain broken down
into 2 parts;
o 2a Design of facility- Qualification of utilities & equipment – Aspect
remains unchanged for us as a department
o 2b Performance qualification approach

- Stage 3: Continued process verification - Ongoing assurance is gained during

routine production that the process remains in a state of control. As prior
indicated becomes holistic ongoing qualification process – ultimately need to
remember that we have the same responsibility for public health welfare as
regulatory inspectors
Stage 1 : Process design

 One of the fundamental Quality Assurance principles is that quality must be

designed into a process from start. Quality cannot be adequately ensured
merely by inspection or sampling and testing. This applies equally to
pharmaceutical manufacturing processes and to the equipment and facilities
used to execute those processes. Facilities and systems must support the
quality requirements of their associated processes in order to be deemed
"suitable for intended use."
 QBD and RA measures in this stage equally need to be supported by process
characterization studies to identify the Key Process Input Variables (KPIV) that
affect Critical-to-Quality (CTQ) measurements for the product. Expectations
include manufacturers to:
 Understand the sources of variation
 Detect the presence and degree of variation
  Understand the impact of variation on the process and ultimately on
product attributes
 Control the variation in a manner commensurate with the risk it represents
to the process and product

Note: Extent of investment in Stage 1 can influence cost and timeline impact for
Stage 2 and scope here needs to be appropriately considered

Stage 2 : Process Qualification

2a Facilities design-utilities equipment qualification

In principle there is no major departure from the old model still dictating that
before being able to undertake Process Performance Qualification;

 Firstly the facility and its supporting critical utilities must be qualified and in a
state of control.
 Secondly, the equipment must be qualified, meaning the installation
qualification, operational qualification and performance qualification are all
complete.
 Finally, the in-process and release methods used for testing must be validated,
and their accuracy and precision well understood, in terms of the final
parameters/limits being evaluated.
Latter point is especially key to ensuring no external analytical variability skews
evaluation and is falsely interpreted as attributed to the process.

2b Process performance equipment qualification (PPQ)

The PPQ exercise focuses on demonstrating process control. Subject to extent of

investment in prior stages, this can determine the level of characterization required
in the PPQ protocol and in doing so departure from old convention of three
consecutive run application, is possible.

Stage 3: Continued process verification

The FDA is looking for a monitoring program capable of detecting gradual or

unplanned departures from the process as designed. Historically used, was the
product stability program, change control process and the Annual Product Review
Process as vehicles for monitoring and assessing process stability. The challenge
with this approach has always been the resolution of these systems making
proactive intervention difficult to achieve when dealing with process drift.

Key point extracts from the PGV document section here, are as follows
  The goal of the third validation stage is continual assurance that the process
remains in a state of control (the validated state) during commercial
manufacture.
 A system or systems for detecting unplanned departures from the process as
designed is essential to accomplish this goal.
 Adherence to the CGMP requirements, specifically, the collection and
evaluation of information and data about the performance of the process, will
allow detection of undesired process variability. Evaluating the performance of
the process identifies problems and determines whether action must be taken
to correct, anticipate, and prevent problems so that the process remains in
control (§ 211.180(e)).
 An ongoing program to collect and analyze product and process data that
relate to product quality must be established (§ 211.180(e)). The data
collected should include relevant process trends and quality of incoming
materials or components, in-process material, and finished products. The data
should be statistically trended and reviewed by trained personnel. The
information collected should verify that the quality attributes are being
appropriately controlled throughout the process.
 Procedures used in measuring and evaluating process stability and process
capability should describe how trending and calculations are to be performed
and should guard against overreaction to individual events as well as against
failure to detect unintended process variability.
 Production data should be collected to evaluate process stability and capability.
The quality unit should review this information. If properly carried out, these
efforts can identify variability in the process and/or signal potential process
improvements.

Janet Woodcock, the FDA director has been particularly instrumental in

driving formal imposition of the above onto industry. Requirement for
upfront submission of Quality - Production-metrics is fast becoming
entrenched.

6. SVP STATUS IN RELATION TO SHIFT - INTERPRETATION AND APPLICATION OF NEW

EXPECTATIONS:
Essentially nature of parenteral drug, administration route and associated heightened
control demands, is such that the parenteral industry here has
knowingly/unknowingly long aligned itself to much of key aspects of the third stage of
the “new” approach and is accordingly ahead of other dosage format facilities
With FDA latest published update to their Process Validation guidance document
(PVG) now:
 based on already established and accepted ICH 8, 9 & 10 principles
 with increased adoption by regulatory agencies/bodies including PIC,
it requires only a degree of context setting in much of cases for SVP
SVP PVG status/insight
 Examples of SVP alignment with requirements include:
 An extensive environmental monitoring (EM) program including continuous active
viable and non viable monitoring at multiple key locations with review built into
batch release
 Formalized MDD SOP in place for immediate carryover of any microbial excursion
event and subsequent tracking and control measures. (Criticality of EM to
parenteral manufacture is such that it dictates for dynamic review systems with
immediate action/proactive approach to raised issues).
 Established EM database, spreadsheet structures and monthly EM review report
reporting process, making for easy EM historical review as well, as affirmation of
current continued personnel, area control & capability to maintain low
contamination incidence.
 Enhanced non viable particulate monitoring systems with automated data
capture, facilitated reporting mechanisms and translation into graphic plot
providing for at glance trending evaluation and decision making processes
 Well structure process simulation challenge in the form of media fill which goes
beyond production risk norms
 Established HEPA filter systems requalification program
 Established building management system (BMS) with live key data display panels
inside and outside key Production & Laboratory areas plus remote access in
centralized engineering, production offices. Features include visual and SMS
alarming notification
 Batch to batch basis - batch book incorporated review and verification of critical
Compounding, Filtration, Cleaning In place (CIP), Sterilization in place(SIP),
Autoclave sterilization and Dry heat tunnel/oven sterilization Control Parameters
 In addition to industry convention control systems including Deviation & Change
control, Aspen SVP also has a “First line feedback report” procedure as further
supporting/precursor report mechanism to Job cards, Deviation/Change control
and to provide for facilitated information screening/ carryover means. Specifically
this procedure allows for initiation of report by the broader workforce, of
observed/perceived equipment/process deficiency. Too often, direct experience of
the employee, either involved at the rock face of task, or providing a secondary
service to the department, is either not volunteered or taken into consideration.
This procedure provides for and encourages wider participation in problem
identification and resolution.
 Well established, comprehensive Quality Systems Review process in place with
purpose of verifying continued compliance and state of control – Review process
is all encompassing of different functions and departments with potential for
impact on process/product quality

SVP PVG outstanding measures

  Still incomplete incorporation of some control data into “live” Quality
Management Systems - part handicap to immediate capture of some of the day
to day events that do occur in real life production, record and reaction to which
form critical part of process control
 Still to be developed/finalized mechanisms to be incorporated into the continuous
verification process include:
 Listing of real/near time(in/on/at line) monitoring of critical process parameters
to ensure all aspects are covered
 Trending of chemical assay results – part handicapped at the moment with no full
LIMS system in place
 Component control statistics – Lot acceptance/rejection profile on receipt and in
process (Initially approved)
 Deviation review as per QSR but extended to provide detail on repeated deviation
circumstances
 Enhanced productivity reporting processes have been developed but full
integration of Production performance metrics must still occur. are in place but –
Requires additional software-hardware introduction to enhance and d formalize
use of existing Electronic display boards (EDB) This to provide:
 Personnel with process- productivity insights by means of at glance live line
performance statistics
 Facilitated reconciliations
(Literature examples of operational expectations wrt performance metrics
include:
- Conformance to the quality plan
- Quality back log
- Through runner equivalent
- OEEs
- Percentage unit rejections at different stages
- Yield variance)
 Engineering report on general machine uptime- insight into any significant
breakdown and preventative measures if any
Message here includes that:
 SVP has been forward looking
 Recognition has always been there that information should always be on
hand and if asked for cannot be withheld
7. KNOWLEDGE MANAGEMENT
 Underlying the new guidance is the stated need for proactively establishing a
system for knowledge management. This means ensuring all parties involved in the
development, analysis and ongoing evaluation of the data and process have a solid
understanding of past and present performance and its implications on process
stability and product performance
 Knowledge management fast assuming same significance in regulatory eyes as risk
assessment
 Recognize that drive for underlying knowledge sharing – knowledge management
aspects to problem resolution, is not only an internal but also external GMP –
Regulatory requirement

 Primary goal for Process validation stage 3 of continuous process verification,

is continual assurance that the process remains in a state of control (the
validated state) during commercial manufacture.
 Below pictogram extract from the 2014 PDA Technical report

8. KEY CONCLUDING STATEMENTS

 Process validation is now encompassing of all validation activities
 Production performance metrics form part of validation life cycle
 Continuous process verification overrides any at interval validation
qualification processes in terms of providing process assurance
 Responsibility for process validation no longer exclusively resides with
Technical/validation departments. “It’s not my job” statements” no longer
apply or can be entertained)
 New expected approach wherein the Product knowledge file encompasses
Tech transfer, Engineering know how, Productivity metrics, Quality metrics,
Continued Process verification, Process trending – tracking, measures provides
for more integrated insight,
 Requires review of older convention model drawing on Technology Transfer
documentation approach with process history and learnings over reliant on
 retrospective use of the Annual Product Quality Review as knowledge
reservoir
 Live control data is invaluable but not rigid requisite for CPV – key issue is
that data collection and processing must be formally undertaken, controlled,
reported and acted on at pre determined intervals such that it allows for
adequate process interpretation and prediction outcome