1. Process Validation – What the Future Holds
Presented by: Karen S Ginsbury
PCI Pharmaceutical Consulting Israel Ltd.
For IFF
February 2011

2. 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

3. 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

4. To be discussed…
The GMP regulations: - EU on Product Quality Review and Process Validation - US on Annual Product Review and Process Validation
Q10 – Pharmaceutical Quality System: Ongoing Process and Product Performance Monitoring
FDA Process Validation guidance

5. 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

6. To be discussed… Organizational Structure, escalation policy SOPs
CAPA and Follow-up
Critical systems, support systems
Management involvement / commitment
Mobilizing resources

7. 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

8. The future is now

9. 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1 Further information on FDA's current thinking on process validation is available in Food and Drug Administration, Draft Guidance for Industry, Process Validation: General Principles and Practices November 2008, available at

10. The Future is Now

11. The Future is Now

12. Regulatory Basis for Validation USA / FDA
Sec 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

13. 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

14. Warning Letters

15. 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

16. Uncertainty
“It is not enough to satisfy the customer… You MUST delight them” W. Edwards Deming

17. 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

18. Production Yield (Y) is a CQA affected by the Variable Inputs (X)
People
Equipment
Measurement
Process
Materials
Environment I N P U T S
(X)
y = ƒ(x)
OUTPUT y
Inputs to the process
control variability
of the Output
Adapted from slide by Moheb Naser, FDA
Quality Attributes
Process Parameters 18

19. From the FDA Guide
CGMP regulations require that batch samples represent the batch under analysis e.g. § (b)(3) and that the sampling plan result in statistical confidence § (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

20. 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

21. 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

22. 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

23. 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

24. 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

25. Life Cycle Approach PROCESS VALIDATION
Identification of process variables
Control strategy
Process qualification
Process monitoring and improvement
Process design
PROCESS VALIDATION

26. No more magic #3!

27. 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

28. Process Validation - EU

29. 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

30. 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:
Technology Transfer “This knowledge [from tech transfer] forms the basis for manufacturing process, control strategy, process validation approach and ongoing continual improvement”

31. 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”

32. 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

33. 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?

34. Revised Process Validation Guide
Three phases to the validation:
Process Design
Process Qualification
Continued Process Verification
Lifecycle Approach
No more magic “three”
Can use data from lab scale / pilot batches to support process qualification

35. FDA Process Validation Guide
Stage
Purpose
Activities
Process Design
Define commercial process based on knowledge gained through development and scale up activities
Outcome: 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

36. 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

37. 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

38. 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 activities This is a pre-requisite for process validation

39. Process Qualification
During the process qualification the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements:
Design of facility and qualification of equipment and utilities
Process Performance qualification (PQ)

40. Continued Process Verification
Ongoing assurance is gained during routine production that the process remains in a state of control

41. Continued Process Verification

42. Ongoing Verification / Reports / CAPA
Change Control
Validation / Calibration Status
Maintenances
Batch Records (statistics)
Audits
Stability
Complaints
Annual Product Review
Critical Systems Review
Environmental Monitoring
OOS / Out of trend results
Deviations (planned / not)
Rejected Batches

43. Demonstrating Ongoing Control
A 10 year old car will not perform in the same manner as a brand new one
BUT if you can demonstrate, by ongoing process monitoring that product performance is unchanged (within the limits of the specification) then the old car is still validated

44. Demonstrating Ongoing Control
Which means looking after the equipment:
Maintenance records: preventive and breakdown
Cleaning records
Use logs
Calibration logs
And periodically performing review of the logs looking for:
Increased frequency / severity of breakdown
Failed calibrations
Failed or non-conforming batches of product
Borderline product – close to specification

45. 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?

46. Quality Review - GMP Requirements
USA
21 cfr part 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]

47. 21 cfr (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:

48. 21 cfr (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 for each drug product.

49. 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

50. (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

51. 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.

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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 improved was it improved / worse than previous year where are the most losses? Why? E.g. visual inspection

61. 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

62. What parameters should be included 6
Review of finished product data:
LOD
assay
Uniformity of content pH
impurities?
OVIs?
other

63. 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

64. 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

65. 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?

66. Q10 – Pharmaceutical Quality System June 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

67. 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

68. Q10 Management Responsibility
Management should assess the conclusions of periodic reviews of process performance and product quality and of the pharmaceutical quality system

69. 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

70. 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

71. 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

72. 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

73. 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

74. SOP Purpose Responsibility Procedure Limits and Limitations
Corrective Actions
Documentation

75. 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

76. 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?

77. Management Involvement
21 cfr (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 (complaints), (returns), (salvaging), any recalls, reports of inspectional observations or any regulatory actions relating to GMP…..
Management needs to be informed of outcome of annual review

78. Management Involvement
Management needs to provide the resources to implement corrective actions
Means:
people
equipment
time
production down time

79. FDA - Risk based Approach to cGMP

80. 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

81. Conclusion Process Validation is a continuum not a one time event
It should encompass the product lifecycle
It 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

82. Thank you for your attention
Questions?