1. Evaluating Product Characteristics for Acceptance
Mark D. Johnson, PMP
ASQ CMQ/OE & CQE
AbbVie Inc.

2. Midwest Biopharmaceutical Statistics Workshop
Agenda
Product Characteristics
Defect Rating Criteria
Sampling Techniques
Questions
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

3. Product Characteristics
Identify characteristics important to confirming product performance
These might be items such as:
Component dimensions for device components
Content uniformity for tablets
Potency and impurities for a drug product lot
Force to activate an autoinjector
Correct tablet coloring for different dosage strengths of same product
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

4. Product Characteristics
Product characteristics can be based on:
Compendial performance expectations
Current quality attribute testing for a similar product
New tests required to assess unique features of a new product
Product features designed to address specific user needs
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

5. Defect Rating Criteria
When a pharmaceutical, medical device or combination product is defective, three defect types are possible:
Design - the pharmaceutical was manufactured correctly, but anticipated or unanticipated side effects caused by the drug use resulted in patient harm or injury; the medical device was poorly designed or not properly tested, creating a situation where the products might be defective and dangerous.
Manufacturing - the product was designed to meet requirements, but manufactured improperly or contaminated somehow during the manufacturing process, potentially exposing the patient to harm.
Marketing – the product’s instructions, warnings, or recommendations for the use of the drug are not sufficiently clear or appropriate to help consumers use the product correctly.
Reference: HG.org Legal Resources Website
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

6. Defect Rating Criteria
Examples of the three defect types are:
Design – An infusion pump screen design is cumbersome or confusing to users, which causes a delay in therapy. For example, the “Start Infusion” key may be located next to the “Power” key, and a user may turn off the infusion pump and lose programmed pump settings instead of initiating infusion. In some cases, programmed settings are lost when a user turns the pump off, and the infusion settings have to be re-entered after the pump restarts.
Manufacturing – Excess water has entered a drug substance batch manufacturing run, due to a faulty valve in the purified water system. This resulted in elevated impurity and reduced potency levels within the batch.
Marketing – A patient does not adequately comprehend the medication’s use instructions that require him to eat a meal and drink water prior to taking his daily dose.
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

7. Defect Rating Criteria
Product characteristics need to be examined to determine the impact of not meeting their acceptance criteria
These characteristics might be based on similar attributes assessed for a comparable product
Likewise, they may be identified and confirmed during the Process Validation Lifecycle activities recommended to document development, verification, validation and future manufacture of the product
This examination may be based on evaluating the impact of the defect upon product functionality or clinical effect to a user
Also, risk-based evaluation can be used to identify the impact of a product defect
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

8. Defect Rating Criteria
Product sampling based on identification of defects was initially used in the Aerospace industry
This approach was adopted within the pharmaceutical industry in the 1970s and 1980s
There is no industry-wide consensus on a specific percent defective level used to characterize Critical, Major, Minor or Cosmetic defects
Dr. Wayne Taylor, a recognized sampling expert, cited the following percent defective levels were commonly used to assess medical devices for product defects:
Critical (Health and Safety): 0.065%, 0.1%, 0.25%
Major (Functional): 0.25%, 0.4%, 0.65%, 1.0%
Cosmetic: 2.5%, 4.0%
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

9. Defect Rating Criteria
Product Attribute
Typical Assigned AQLs
Critical
0.04%, 0.065%, 0.1%, 0.15%, 0.25%
Major Functional
0.25%, 0.4%, 0.65%, 1.0%
Minor Functional
0.65%, 1.0%, 1.5%
Cosmetic Visual
1.5%, 2.5%, 4%, 6.5%
Acceptance Quality Limits (AQLs) in Pharma / Devices
These attribute categories help identify the foci of our sampling activities.
Are we only interested in assessing superficial product characteristics, or do we need to assess critical product operations or functions as well?
We use these attribute categories to assure our processes operate to meet or surpass our expectations for observing defective product.
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

10. Defect Rating Criteria
Defect rating criteria may be defined as:
Critical: A nonconformity likely to present a hazard to health
Major Functional: A nonconformity which may cause the product to be unfit for use, significantly degrades its function or performance, or is likely to generate a complaint
Minor Functional: A nonconformity which may cause the product to function poorly or a user inconvenience, but may still be fit for use, or possibly generate a complaint
Cosmetic Visual: A nonconformity detrimental to the high quality image of a product that will not affect usability or functionality, but affects only appearance of the product
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

11. Defect Rating Criteria
These criteria can be based on:
Similar defects experienced with a similar product
Historically observed defects for the product’s dose modality (e.g., oral solution, tablets, capsules)
Risk-based assessment of hazardous situations/failure modes experienced with the product
Means of evaluating product performance vs. current test methods or other necessary standards
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

12. Defect Rating Criteria
Assessment of these criteria is completed by:
Laboratory testing of product vs. required quality attributes
Functional testing of product to meet operational requirements
Visual examination for any noticeable defects
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

13. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
To assess product characteristics, an adequate sample of sufficient confidence must be used
Based on the defect level of the characteristic of interest, different confidence levels might be considered for validation purposes:
Critical (e.g., % defective ≤ 0.4%), validate to ≥ 90% confidence
Major (e.g., 0.40% < % defective ≤ 2.5%), validate to ≥ 50% confidence
Minor (e.g., % defective > 2.5%) validate to ≥ 20% confidence
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

14. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Similarly for process validation activities, an adequate level of confidence is also required:
New process/product or major process change, validate to ≥ 90% confidence
Routine revalidation, validate to ≥ 50% confidence
Minor process change or accelerated testing, validate to 20-50% confidence
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

15. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
There are different methods available to sample product for inspection:
Simple Random Sampling – Selecting samples so that each unit has an equal chance of being selected
Stratified Random Sampling – Selecting samples deliberately from each time period or location in a batch
Nested Sampling – Selecting units from locations within a batch and obtaining multiple samples from each location
Systematic sampling – Selecting units periodically over time
Three methods for sampling are shown here. We will discuss each, and explain how it may or may not be correctly used in a validation sampling plan.
Sampling point = a physical place or a specific point in time.
WHERE WHEN
Each sampling method is described in the following slides.
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

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Sampling Techniques
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

17. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Validation vs. Product Acceptance Sampling Plans – What are the differences?
Validation Sampling
Cannot assume process is good, because it has not been validated yet
Need to prove it's good
"Guilty until proven innocent“
Need to use tighter sampling plan than one used for product acceptance (e.g., will reject when data shows high confidence (e.g., 90% or 95%) that product performance vs. acceptance criteria is worse than acceptable % defective)
Product Acceptance Sampling
Assumes process is good, since process successfully validated
"Innocent until proven guilty“
Will only reject when data shows low confidence (e.g., 5-10%) product performance vs. acceptance criteria is worse than the AQL
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

18. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
If you pass the “n=575, a=0” PPQ sampling plan, you have 90% confidence (e.g., (1-0.1 Pr(Accept)*100%) you will accept a lot ≤ 0.4% Defective.
If you pass the “n=32, a=0” Product Acceptance sampling plan, you have 12% confidence (e.g., ( Pr(Accept)*100%) you will accept a lot ≤ 0.4% Defective.
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

19. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Once the process has been validated, the confidence of the sampling plan can be relaxed to routinely assess batches for large quality defects.
ANSI Z1.4 provides attribute sampling plans to be used for routine lot inspection and acceptance
ANSI Z1.9 provides variables sampling plans to be used for routine lot inspection and acceptance
Both plans provide switching rules for transitioning from normal to tightened, tightened to normal, normal to reduced and reduced to normal sampling practices, dependent on the continuing documented quality history of the product
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

20. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Once you’ve determined the product characteristics to assess vs. their required acceptance criteria, you can build a sampling approach
Two types of sampling plan approaches typically used:
Attributes: units assessed within each sample can only pass or fail the acceptance criteria
Variables: mean and standard deviation are calculated for a sample of units, then a range is calculated using a factor suitable to the defect level and sample size for comparison with the acceptance criteria
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

21. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Attribute characteristic examples:
Fill volume: >20 mL
Tablet defects: cracked, chipped
Extraneous matter: visible particulate, rubber, hair
Variables characteristic examples:
Component dimensions: Length = 2 ± 0.25 mm
Ejection force: ≤ 10 Newtons
Crush test for tablet: ≥ 100 Newtons
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

22. Midwest Biopharmaceutical Statistics Workshop
Sampling Techniques
Attribute Sampling:
Easy to conclude result, either pass/fail
Many samples might be required to provide adequate confidence in pass/fail decision
Variables Sampling:
Variables data contains more information than percent nonconforming
More descriptive
More statistical information and power
Fewer samples required for same statistical power
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

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Sampling Techniques
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Midwest Biopharmaceutical Statistics Workshop

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Sampling Techniques
20 May 2015
Midwest Biopharmaceutical Statistics Workshop

25. Midwest Biopharmaceutical Statistics Workshop
Questions…
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Midwest Biopharmaceutical Statistics Workshop

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Thank You!
20 May 2015
Midwest Biopharmaceutical Statistics Workshop