process validation – what the future holds presented by: karen s ginsbury pci pharmaceutical...
TRANSCRIPT
![Page 1: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/1.jpg)
Process Validation – What the Future Holds
Presented by: Karen S GinsburyPCI Pharmaceutical Consulting Israel Ltd.
For IFFFebruary 2011
1
![Page 2: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/2.jpg)
Course Objective
Take an in depth look at the regulatory requirements (EU and FDA) for process validation– FDA process validation guidance– Q10 – Pharmaceutical Quality System
Guidance • Management Review • Ongoing product and process performance
monitoring
2
![Page 3: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/3.jpg)
The Objective…
• Gain an overall understanding of the topic of Process Validation over a product lifecycle tied in with Product Quality Review in the context of ongoing verification of process and product performance
• Tie in with CAPA programs to provide an enhanced quality system
3
![Page 4: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/4.jpg)
To be discussed…
• The GMP regulations:- EU on Product Quality Reviewand Process Validation- US on Annual Product Reviewand Process Validation
• Q10 – Pharmaceutical Quality System:Ongoing Process and Product Performance Monitoring
• FDA Process Validation guidance
4
![Page 5: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/5.jpg)
To be discussed…
• What industry is currently doing• Critical Process Parameters and their review• Critical Quality Attributes and their inclusion
in the review• Data trending (Use of simple statistical tools)• Validation, deviations and changes
5
![Page 6: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/6.jpg)
To be discussed…
• Organizational Structure, escalation policy• SOPs• CAPA and Follow-up• Critical systems, support systems• Management involvement / commitment• Mobilizing resources
6
![Page 7: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/7.jpg)
Purpose of Validation:
• To satisfy the regulators!!• Ensure you got what you intended• In accordance with design / development• Map critical elements / show reproducibility• Allow for:
– Continuous Improvement / Change management– Ongoing maintenance– Ongoing qualification– CAPA
![Page 8: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/8.jpg)
The future is now
![Page 9: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/9.jpg)
The future is now
• Your firm failed to provide validation protocols that evaluated the impact of the increasing batch sizes on product quality. You failed to conduct a study to demonstrate at what point each batch size is uniformly blended. You have not conducted any analysis comparing data between your validation batches. Further, your firm uses a general "Master Validation Plan" for process validation on all products. Validation must be demonstrated for each product and process. The critical controls and processing parameters must be known and shown to be in control, and a demonstration of process reproducibility with objective measures must be made.1
• 1 Further information on FDA's current thinking on process validation is available in Food and Drug Administration, Draft Guidance for Industry, Process Validation: General Principles and Practices November 2008, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf
![Page 10: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/10.jpg)
The Future is Now
10
![Page 11: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/11.jpg)
The Future is Now
11
![Page 12: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/12.jpg)
Regulatory Basis for Validation USA / FDA
Sec. 211.68 Automatic, mechanical, and electronic equipment • “Automatic, mechanical, or electronic equipment or other types of equipment,
including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product
• Such equipment shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those … inspections shall be maintained”
• Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system
![Page 13: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/13.jpg)
Regulatory Basis for Validation – EU
Annex 15 – Qualification and Validation (2001)• …a GMP requirement that manufacturers identify what
validation work is needed to prove control of critical aspects of their particular operations
• Significant changes to facilities, equipment and processes, which may affect the quality of the product, should be validated
• A risk assessment approach should be used to determine the scope and extent of validation
![Page 14: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/14.jpg)
Warning Letters
14
![Page 15: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/15.jpg)
Some Concepts• Uncertainty: The lack of certainty, A state of
having limited knowledge where it is impossible to exactly describe existing state or future outcome or there is more than one possible outcome
• Measurement of Uncertainty: A set of possible states or outcomes where probabilities are assigned to each possible state or outcome
• Risk: A state of uncertainty where some possible outcomes have an undesired effect or significant loss
![Page 16: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/16.jpg)
Uncertainty“It is not enough to satisfy the customer…
You MUST delight them” W. Edwards Deming
![Page 17: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/17.jpg)
Two More that have to be understood
Critical Quality Attribute (CQA):• A physical, chemical, biological or microbiological
property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
[= safety, efficacy, performance]Critical Process Parameter (CPP):• A process parameter whose variability has an impact
on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality
17
![Page 18: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/18.jpg)
Production Yield (Y) is a CQA affected by the Variable Inputs (X)
18
People
Equipment
Measurement
Process
Materials
Environment
INPUTS
(X)
y = ƒ(x)
OUTPUT
y
Inputs to the process
control variabilityof the Output
Observation
Indiv
idual V
alu
e
4038363432302826242220
120
115
110
105
100
95
90
_X=102.37
UCL=116.68
LCL=88.05
I Chart
Observation
Indiv
idual V
alu
e
6058565452504846444240
115
110
105
100
95
90
85
80
_X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Indiv
idual V
alu
e
8078767472706866646260
115
110
105
100
95
90
_X=99.63
UCL=111.55
LCL=87.71
I Chart
Observation
Indiv
idual V
alu
e
10098969492908886848280
110
105
100
95
90
85
_X=98.76
UCL=111.17
LCL=86.35
I Chart
Observation
Indiv
idual V
alu
e
6058565452504846444240
115
110
105
100
95
90
85
80
_X=97.94
UCL=112.65
LCL=83.23
I Chart
Observation
Indiv
idual V
alu
e
8078767472706866646260
115
110
105
100
95
90
_X=99.63
UCL=111.55
LCL=87.71
I Chart
Observation
Indiv
idual V
alu
e
9181716151413121111
115
110
105
100
95
90
85
_X=99.95
UCL=114.17
LCL=85.72
I Chart
Adapted from slide by Moheb Naser, FDA
Process
ParametersQuality
Attributes
![Page 19: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/19.jpg)
From the FDA Guide
• CGMP regulations require that batch samples represent the batch under analysis e.g. § 211.160(b)(3) and that the sampling plan result in statistical confidence § 211.165(c)
• in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate” This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability
![Page 20: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/20.jpg)
From the Guide
• We recommend an integrated team approach to process validation that includes expertise from a variety of disciplines, e.g. process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance
![Page 21: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/21.jpg)
From the Guide
• The approach to PQ should be based on sound science …
• we strongly recommend firms employ objective measures (e.g., statistical metrics), wherever feasible and meaningful to achieve adequate assurance
![Page 22: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/22.jpg)
From the Guide
• In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance
• The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during processing
![Page 23: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/23.jpg)
From the Guide• The increased level of scrutiny, testing, and sampling
should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process
• Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to:– volume of production– process complexity– level of process understanding– experience with similar products and processes
![Page 24: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/24.jpg)
From the Guide
• The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies
• The usable lifetimes of such materials should be confirmed by an ongoing PPQ protocol during commercial manufacture
![Page 25: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/25.jpg)
Life Cycle Approach
PROCESS VALIDATION
![Page 26: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/26.jpg)
No more magic #3!
![Page 27: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/27.jpg)
Process Validation – FDA
• Current Process Validation is from 1987• Guidance is out-dated and no longer reflects
current GMPs• The new document is closer to ICH Q8, 9 and
10 philosophy of lifecycle approach to product (risk) management
![Page 28: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/28.jpg)
Process Validation - EU
![Page 29: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/29.jpg)
Process Validation - EU• The current guideline was developed before ICH Q8/9/10• Additional means are available to verify the control of the process
by alternative means to the traditional process validation batches• The main objective is that a process design yields a product meeting
its pre-defined quality criteria• Q8/9/10 provide a structured way to define CQAs, design space,
manufacturing process and the control strategy• Continuous process verification can be utilised in process validation
protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle
![Page 30: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/30.jpg)
Surprised?…You Shouldn’t be!
• Q10, section 1.6 Enablers:– 1.6.1 Knowledge management
“…process validation studies over the product lifecycle”
• Q10, section 3.1 Lifecycle Stage Goals:– 3.1.2 Technology Transfer
“This knowledge [from tech transfer] forms the basis for manufacturing process, control strategy, process validation approach and ongoing continual improvement”
![Page 31: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/31.jpg)
Surprised?…You Shouldn’t be!
• Q10, section 3.2 Quality System Elements:– 3.2.1 Process Performance and Product Monitoring
System“…provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation”
![Page 32: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/32.jpg)
Definition: 1987 Guide
• Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics
![Page 33: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/33.jpg)
Current Definition: January 2011
Proposed definition:process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product
Preapproved Protocols?Completion of Optimization?
![Page 34: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/34.jpg)
Revised Process Validation Guide
• Three phases to the validation:1. Process Design2. Process Qualification3. Continued Process Verification
• Lifecycle Approach• No more magic “three”• Can use data from lab scale / pilot batches to
support process qualification
![Page 35: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/35.jpg)
Stage Purpose Activities
Process Design Define commercial process based on knowledge gained through development and scale up activitiesOutcome: design a process for routine manufacture that will consistently deliver product meeting its critical quality attributes
Integrated product and process design Product development activities DOE combined with Risk Assessment
to explore process parameters, variability, effect on quality attributes and process controls
Process
Qualification
Confirm process design as capable of reproducible commercial manufacturing
Facility design Equipment & utilities qualification Performance qualification Emphasis on use of statistically based
sampling plans, statistically valid acceptance criteria and statistical analysis of process data to understand process consistency and performance
Continued Process Verification
Provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives
Organized data collection every batch Data trending and statistical analysis Product review Equipment and facility maintenance Calibration Management review and production Employee feedback Continuous improvement
FDA Process Validation Guide
![Page 36: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/36.jpg)
Worst Case
• A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions
• Such conditions do not necessarily induce product or process failure
- Annex 15 glossary
![Page 37: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/37.jpg)
FDA Guide
• Each step of a manufacturing process is controlled to ensure that the finished product meets all design characteristics and quality attributes including specifications
• Each step of a manufacturing process is controlled (Product Control Strategy) to assure that the finished product meets its Critical Quality Attributes and Performance Characteristics as defined in the Quality Target Product Profile
![Page 38: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/38.jpg)
Stages of Validation - Process Design
Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activitiesThis is a pre-requisite for process validation
![Page 39: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/39.jpg)
Process Qualification
• During the process qualification the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements:
1.Design of facility and qualification of equipment and utilities
2.Process Performance qualification (PQ)
![Page 40: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/40.jpg)
Continued Process Verification
• Ongoing assurance is gained during routine production that the process remains in a state of control
40
![Page 41: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/41.jpg)
Continued Process Verification
![Page 42: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/42.jpg)
Ongoing Verification / Reports / CAPA
• Complaints• Annual Product Review• Critical Systems Review• Environmental Monitoring• OOS / Out of trend results• Deviations (planned / not)• Rejected Batches
• Change Control• Validation / Calibration
Status• Maintenances• Batch Records (statistics)• Audits• Stability
![Page 43: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/43.jpg)
Demonstrating Ongoing Control
• A 10 year old car will notperform in the same manneras a brand new one
• BUTif you can demonstrate, byongoing process monitoringthat product performanceis unchanged (within thelimits of the specification)then the old car is still validated
![Page 44: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/44.jpg)
Demonstrating Ongoing Control
• Which means looking after the equipment:– Maintenance records:
preventive and breakdown– Cleaning records– Use logs– Calibration logs
• And periodically performingreview of the logs looking for:– Increased frequency / severity of breakdown– Failed calibrations– Failed or non-conforming batches of product– Borderline product – close to specification
![Page 45: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/45.jpg)
What about Grandfather Products
• Grandfather products shouldn’t be a concern: Product Quality Review and vast knowledge accumulated over years should provide an excellent basis for ongoing process validation – if you don’t have it already…you should have (more or less)But – new products, IMPs…when will regulators expect to first hear the term Process Validation and see data?
![Page 46: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/46.jpg)
Quality Review - GMP Requirements
• USA– 21 cfr part 211.180 General Requirement
section (e)– EU Guide– Chapter 1 to the EU Guide to Good Manufacturing
Practice (October 2005)[since updated to include Quality Risk Management]
46
![Page 47: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/47.jpg)
21 cfr 211.180 (e)Written records required by this part shall be maintained so that data therein can be used for evaluating at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:
47
![Page 48: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/48.jpg)
21 cfr 211.180 (e) cont/(1) A review of a representative number
of batches, whether approved or rejected, and where applicable, records associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product.
48
![Page 49: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/49.jpg)
Chapter 1 – (1.4) Product Quality Review
• Regular periodic or rolling quality reviews of all licensed medicinal products,
• including export only products• Such reviews should normally be
conducted and documented annually, taking into account previous reviews
49
![Page 50: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/50.jpg)
(1.4) PQR Objective
Verify• The consistency of the existing process• The appropriateness of current specifications
for:– starting materials
and– finished product
to highlight any trends and to identify product and process improvements
50
![Page 51: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/51.jpg)
Include at least…
(i) A review of starting materials including packaging materials used in the product, especially those from new sources
(ii) A review of critical in-process controls and finished product results
(iii) A review of all batches that failed to meet established specification(s) and their investigation.
(iv) A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken.
51
![Page 52: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/52.jpg)
Include at least…
(v) A review of all changes carried out to the processes or analytical methods
(vi) A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers
(vii) A review of the results of the stability monitoring programme and any adverse trends
(viii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time
52
![Page 53: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/53.jpg)
Include at least…
(ix) A review of adequacy of any other previous product process or equipment corrective actions
(x) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments
53
![Page 54: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/54.jpg)
Include at least…
(xi) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.
(xii) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date
54
![Page 55: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/55.jpg)
Chapter 1 continued…
• The manufacturer and marketing authorisation holder should evaluate the results of this review, where different, and an assessment made of whether corrective and preventative action or any revalidation should be undertaken
55
![Page 56: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/56.jpg)
Chapter 1 continued…
• Reasons for such corrective actions should be documented
• Agreed corrective and preventative actions should be completed in a timely and effective manner
• There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self inspection
56
![Page 57: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/57.jpg)
What parameters should be included• Number of batches manufactured• Number of batches released• Number of batches rejected• Number of batches in quarantine / hold• More / less than previous year? Why?• Comments
57
![Page 58: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/58.jpg)
What parameters should be included 2• Raw Materials specifications• Raw Materials manufacturers (changes at
least)• Raw Materials: batch numbers used for:
– API– Key excipients?
• Product specifications• Review of batch records
58
![Page 59: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/59.jpg)
What parameters should be included 3• Review of manufacturing data:
– were there changes in:• facility• raw material suppliers?• equipment• manufacturing instructions?• product specs• test methods?
– If yes, when exactly did the change happen
59
![Page 60: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/60.jpg)
What parameters should be included 4• Review of manufacturing data:
set up charts of data or collect on line– batch yields: theoretical, actual, reconciliation
can the reconciled yield be improvedwas it improved / worse than previous yearwhere are the most losses? Why?E.g. visual inspection
60
![Page 61: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/61.jpg)
What parameters should be included 5• Review of manufacturing data / laboratory
results:– in-process pH, conductivity– in-process assays: before / after filtration– in-process assays: before / after mixing– physical parameters: particle size distribution
other?– Tablet weight, thickness, hardness, friability etc.– Fill volume / uniformity of content
61
![Page 62: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/62.jpg)
What parameters should be included 6• Review of finished product data:
– LOD– assay– Uniformity of content– pH– impurities?– OVIs?– other
62
![Page 63: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/63.jpg)
What parameters should be included• Review related SOPs?• Reserve samples ?• Stability data: to what level of detail?• What are you looking for• Why do you need to do it?
– If the batches are in limits they are released– If not rejected
63
![Page 64: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/64.jpg)
Data Trending• Easiest to assess as line graphs• Average• Standard Deviation• Upper and lower control limits (2 or 3 SDs)• Compared to Upper and lower specification
limits• Can all be done on Excel (what about
validation????)• cf with previous years / similar products
64
![Page 65: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/65.jpg)
Deviations
• Don’t list all deviations• Give an overview• Categorize and look at root causes• Compare with previous years• Up or down e.g. equipment deviations,
maintenance - indicative of aging equipment, consider re-validation? Replacement?
65
![Page 66: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/66.jpg)
Q10 – Pharmaceutical Quality SystemJune 2008
• model for an effective quality management system for the pharmaceutical industry
• that can be implemented throughout the different stages of a product lifecycle
• Product Quality Review is concerned with the PRODUCT LIFECYCLE – ongoing control
66
![Page 67: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/67.jpg)
Q10 Management Responsibility
• Ensure a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management
• Conduct management reviews of process performance and product quality and of the pharmaceutical quality system;
• Advocate continual improvement;• Commit / mobilize appropriate resources
67
![Page 68: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/68.jpg)
Q10 Management Responsibility
• Management should assess the conclusions of periodic reviews of process performance and product quality and of the pharmaceutical quality system
68
![Page 69: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/69.jpg)
Continual Improvement of Process Performance and Product Quality
• Section 3 of Q10 = PQR• 3.1.3 Commercial Manufacturing • The goals of manufacturing activities include …
establishing and maintaining a state of control and facilitating continual improvement
• The pharmaceutical quality system should assure that:– the desired product quality is routinely met– suitable process performance is achieved– the set of controls are appropriate– improvement opportunities are identified and evaluated– the body of knowledge is continually expanded
69
![Page 70: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/70.jpg)
3.2.1 Process Performance and Product Quality Monitoring System • plan and execute a system for the monitoring
of process performance and product quality to ensure a state of control is maintained
• An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement
70
![Page 71: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/71.jpg)
3.2.1 Process Performance and Product Quality Monitoring System
• Use risk management to establish product control strategy• Provide tools for measurement and analysis of parameters and attributes
identified in the control strategy (e.g., data management and statistical tools)• Analyse parameters and attributes identified in the control strategy to verify
continued operation within a state of control• Identify sources of variation affecting process performance and product
quality for potential continual improvement activities to reduce or control variation
• Include feedback on product quality from internal and external sources, e.g., complaints, product rejections, non-conformances, recalls, deviations, audits and regulatory inspections and findings
• Provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation
71
![Page 72: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/72.jpg)
Change Control
• Need ongoing change control• Need change control for changes resulting
from the annual review• Do not assume that because it was written in
the conclusions it can be implemented straight out in production
72
![Page 73: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/73.jpg)
Organizational Structure
• Who does the review?• Get as much as possible from computers• Get production / ops involved - they are the
owners of the process• Make sure that Process Development signs off
on the report - they will need to troubleshoot
73
![Page 74: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/74.jpg)
SOP
• Purpose• Responsibility• Procedure• Limits and Limitations• Corrective Actions• Documentation
74
![Page 75: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/75.jpg)
Follow-up
• Part of CAPA program• Won’t happen on its own• Requires troubleshooting, which means
process development and change control and maybe process validation / revalidation
• Documentation• Approvals
75
![Page 76: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/76.jpg)
Critical Systems Review
• WFI• Purified Water• HVAC system• Clean Steam• Autoclave?• Oven?• Media Fill• (Aseptic Process)
• Validation Program• Audit Program• Training Program• Stability Program?• SOPs• Reserve Samples?
76
![Page 77: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/77.jpg)
Management Involvement
• 21 cfr 211.180 (f) (directly after annual review)• “Procedures shall be established to assure that the
responsible officials of the firm, if they are not personally involved in or immediately aware of such actions are notified in writing of any investigations conducted under 211.198 (complaints), 211.204 (returns), 211.208 (salvaging), any recalls, reports of inspectional observations or any regulatory actions relating to GMP…..
• Management needs to be informed of outcome of annual review
77
![Page 78: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/78.jpg)
Management Involvement
• Management needs to provide the resources to implement corrective actions
• Means:– people– equipment– time– production down time
78
![Page 79: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/79.jpg)
FDA - Risk based Approach to cGMP
79
![Page 80: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/80.jpg)
Ongoing• Critical parameters must be understood• Critical process parameters must be defined• Critical process parameters must have ranges• Trends need to be followed, understood and
acted upon• Change control may need to follow trends
80
![Page 81: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/81.jpg)
Conclusion
Process Validation is a continuum not a one time eventIt should encompass the product lifecycleIt can be tied in with product and process quality reviews
to demonstrate maintenance of an ongoing state of control– a MANAGEMENT tool– an opportunity to correct a process before the process
gets out of hand– a money saving tool if used properly– to be used in investigation of deviations– to be used in estimating effects of changes to the process
81
![Page 82: Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011 1](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649e025503460f94aeccf4/html5/thumbnails/82.jpg)
Thank you for your attention
Questions?
82