Subject: August 2015 Prior Approval Request DoD Serial Number:
Changes Without Prior Approval - Pharma
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Transcript of Changes Without Prior Approval - Pharma
Changes Without Prior Approval
How do we get there from here?
Jon ClarkAssociate Director for Policy DevelopmentOffice of Pharmaceutical ScienceCenter for Drug Evaluation and Research, FDA
ACPS Manufacturing Subcommittee July 21, 2004
Overview
The traditional system of approval and change control seems burdensome
There should be a way to protect the public without slowing innovation
Methods and standards for this are available Need to train ourselves into a new way of thinking
and working
Shared Concerns The pharmaceutical industry has one of the most
technically advanced discovery organizations, but remains more conservative when it comes to using "cutting edge" technology in manufacturing.
Concern over how regulatory agencies will react to using knowledge and technology
Agency focus on changes with inconsequential impact on the product quality can result in delay.
Complex Interaction
Commitment to high quality products
with
Commitment to most rapid introduction to market
When to Optimize the Process Optimization before approval
Greatest cost may be time No baseline for measuring return on investment Provides immediate benefit to patient
Continuous improvement Time element minimized Enables measured improvement Feed forward data and scope protocols
Inclusion of development data helps, but can not equal knowledge obtained during routine production
Points to Consider
Raw Materials Process Measurement Steering the Process Variability
Raw Materials
Pharmaceutical raw materials are variable. Cannot assume that holding the inputs
constant will always produce a constant product.
Ergo: Attempting process control through raw material control is futile.
Process
Discovery and design suggest a process model The model should be designed so that its
parameters can be measured in the real world As the model evolves measurement strategy
evolves with it The effect of change can be better predicted
with realistic models There is a lack of process models in
applications
Measurement
Measurement is most effective when used to control the process in “real time”
Traditional approach has been to sample the process and product, then test for compliance with criteria via “Laboratory Determination”
Steering the Process
Change times, speeds, temperatures based on measurement to achieve target value for a product parameter.
Discarding batches or portions of batches reveals failure to steer the process.
Variability
Variability reduction adds value increases process capability minimizes the risk of OOS prerequisite for investigation
Situation Spectrum
High Process Understanding and Control
Obviated End Product Testing
Extensive Product TestingLittle Process Understanding
Increasing Desirability
Therefore
FDA focus on Laboratory Testing is not ideal for controlling a process
Need to encourage Process Understanding and Engineering
Focus resources on the manufacturing process instead of lab tests and criteria
Avoid trap of “measure it because you can”
Need for Zero Tolerance Limits N
eed
for Z
ero
Tole
ranc
e Li
mits
Increasing Process Understanding and Control
Continuous ImprovementPo
st A
ppro
val
Reg
ulat
ion
Knowledgeand Process Understanding
Current Paradigm
RawMaterial
ProductManufacturing Process
LockedProcess Variables
Variability
Dynamic System
Manufacturing Process
Measurement DependantProcess Variables
RawMaterial
Product
InputResponse
EndpointResponse
P A TProcess Analytical Technology
Manufacturing Process
Critical Process Parameter (CPP)adjusted by measurement of
Critical Quality Attributes (CQA)
RawMaterial
Product
FeedForward Feedback
We are not AloneMIL-STD-1916 dated 1996
“Process controls and statistical control methods are the preferable means of preventing nonconformances, controlling quality, and generating information for improvement.”
“Sampling inspection by itself is an inefficient industrial practice for demonstrating conformance to the requirements of a contract and its technical data package.”
“To the extent that such practices are employed and are effective, risk is controlled and, consequently, inspection and testing can be reduced.”
More
“The objective is to create an atmosphere where every noncompliance is an opportunity for corrective action and improvement rather than one where acceptable quality levels are the ... goals.”
“The goal is to support the movement away from a [product] inspection strategy to … effective prevention-based strategies including a comprehensive quality system, continuous improvement and partnership with Government.”
And More
Process should be focus of quality system Consistently producing conforming product. Controlled as far upstream as possible. Robust to variation…. Operated to constantly reduce variation. Utilization of equipment in a way that minimizes
variability around target values Managed for continuous improvement Designed and controlled using a combination of
practices and methods in order to ensure defect prevention and process improvement.
Product Sampling and QualityDr. W. Edwards Deming
"Cease dependence on inspection [laboratory determination] to achieve quality. Eliminate the need for inspection on a mass basis by building quality into the product in the first place."
"Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive variability in the process. The disease is variability.”
"Ceasing dependence on inspection means you must understand your processes so well that you can predict the quality of their output from upstream activities and measurements."
Target Critical Quality Attributes R
ange
of R
aw M
ater
ial
and
Faci
lity
Attr
ibut
esRange
Process Designed to LimitProduct Variability
CQA
Variation ControlAnna Thornton “Variation Risk Management”
Identification Key Characteristics (KC)
Those that assure achieving CQA Variation “Flowdown”
Assessment Which variations put CQA at risk
Mitigation Eliminate source Reduce impact
Examples of evidence regarding process understanding MIL-STD-1916 dated 1996
Process flow charts showing the key control points for action to prevent defective product
Identification of process improvement techniques…
Identification of measures used, e.g., trend analysis
Results of improvements from using these… Results of experiments that led to reduced
variability...
Examples of evidence regarding process control
Identification of the scope of use of process control techniques…
Process control plans, including improvement goals…
Approaches and supporting data used to determine if suppliers have adequate controls…
Descriptions of the required training … Identification of departmental interrelations Rationale for establishing subgroups Identification of key parameters used in lieu of
specified characteristics More...
Examples of evidence regarding process control (continued)
Identification of personnel responsible for process related corrective action.
Proper gage measurement studies showing measurement variations relative to total variation.
Traceability of the product and process corrective action(s) taken when the process went out of control, showing how the root cause was identified and eliminated.
Examples of evidence regarding product conformance
Control chart showing the process in statistical control in accordance with the criteria…
Records of product and process corrective action(s) taken when nonconformances occur.
Process capability studies consisting of correct calculation and interpolation of [attribute measures]
History of product inspection results reinforced by statistical data and analysis.
Results from in-process control methods, such as [automation applications]
Contribution ofExperience and Quality System
Institutionalization of Knowledge is a Quality Concern Need to apply “solutions” wherever they
provide improvement Prior regulatory approval for every
improvement defeats this goal
Application w/o supplements? What are quality critical attributes, the means of
monitoring and controlling them What are the fundamental scientific mechanisms of
the physical changes? How do formulation and process factors affect
product performance? Control of the operation using mechanistic scientific
principles; Directly! Demonstrate a range of operating ranges, controls
and principles History of manufacturing success with similar drugs
or similar operating principles or similar site operations
More Information
Significance of the site location and environment on the quality of the finished product
Drug product specification based on attributes critical to product performance experienced by the patient
Process control relationships to finished product quality
Operational Freedom This process understanding knowledge leads
to greater freedom from narrow operating procedures and allow focus on drug product quality
Provide for use of alternatives to any application requirements components manufacturing and packaging procedures in-process controls analytical procedures 21 CFR 314.50 (d)(1)(ii)
Focus on process science and understanding
The FDA wishes to avoid allowing the submission of great operating procedure detail with equipment specifications to create a "safe harbor" for processes that do not consistently result in quality of product suitable for use
Batch records should not be used as manufacturing process control specifications or change control restrictions
Stability analysis is more valuable than raw data Understanding of degradation mechanism helps
predict impact of change
Commercial Batch Research Data Agency acknowledges concern that process
research data may indicate a problem when the product still meets its approved release methods.
FDA began using a "research data exemption" concept in several guidance documents. Doesn’t protect one that knowingly does harm
without attempting corrective action. This is designed to place this information outside
the scope of a “normal” inspection. Shouldn’t impact on the ability to release products
that meet all aspects of the company's current registered quality control strategy.
Situation Spectrum
High Process Understanding and Control
Obviated End Product Testing
Extensive Product TestingLittle Process Understanding
Increasing Desirability
End
Thank you