Continuous Flow Mfg Skip-Lot Sampling Domenick Amato Frank Gomez Lynn Torbeck

21 CFR (20) “Acceptance Criteria means the product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level with an associated sampling plan …” 210.3(20) “Acceptance Criteria means the product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level with an associated sampling plan …” 210.3(21) Representative samples 210.3(21) Representative samples

21 CFR Requirements: Requirements: 1.Representative samples 2.Number of containers to sample 3.Amount of material to be taken 4.Variability – Process average 5.Confidence levels 6.Past quality history

Continuous Flow Mfg How to define a continuous process? Types of processes? How to define a continuous process? Types of processes? How to define a “lot” or “batch” in a continuous flow process? How to define a “lot” or “batch” in a continuous flow process? Assumption of homogeneity of product? Assumption of homogeneity of product? Assumptions about defects? Assumptions about defects?

Types of Sampling Plans Variables Plans: Variables Plans: ANSI/ASQ Z1.9ANSI/ASQ Z1.9 Attribute Plans Attribute Plans ANSI/ASQ Z1.4ANSI/ASQ Z1.4 ISO 2859ISO 2859

Sampling Plans Defined Population of units, lots or batches Population of units, lots or batches AQL: Acceptable Quality Limit AQL: Acceptable Quality Limit LQ: Unacceptable Quality Limit LQ: Unacceptable Quality Limit Sample size Sample size Accept number Accept number Reject number Reject number

Risk Management “Producer’s Risk” The probability that a good lot is rejected by the customer. (Type I error or alpha) “Producer’s Risk” The probability that a good lot is rejected by the customer. (Type I error or alpha) “Consumer’s Risk” The probability that a bad lot is accepted by the customer. (Type II error or beta) “Consumer’s Risk” The probability that a bad lot is accepted by the customer. (Type II error or beta) Levels not fixed but common values are 5% and 10%. Levels not fixed but common values are 5% and 10%.

Assumptions for Sampling Representative samples Representative samples Beginning, middle and endBeginning, middle and end Top, middle and bottomTop, middle and bottom Every 30 minutes or 100 unitsEvery 30 minutes or 100 units Random Sampling – (difficult)Random Sampling – (difficult) Defects must be randomly distributed ! Defects must be randomly distributed ! Sample inspection is 100% Sample inspection is 100%

Reduced Testing 1. Smaller sample size. Using General Inspection Level I in place of Level II or III in Z Not inspecting all characteristics on the CoA or listed in the USP. 3. Can use reduced testing in Z Use the switching rules in Z1.4.

Skip-Lot Sampling Not all lots are tested. Not all lots are tested. Only a fraction of lots are inspected. Only a fraction of lots are inspected. Goal is to save money or time and still achieve quality products. Goal is to save money or time and still achieve quality products.

Types of Skip-Lot Sampling 1. Test every “n th ” lot, not random. 2. Test “i” lots, if all pass go to a fraction, “f”, of future lots. Select i and f in advance. Lots selected at random. 3. ASQ S1, i and f are determined from the data collected. Lots are selected at random using dice.

Assumptions for Skip-Lot Supplier and customer agree on a plan. Good communications. Supplier and customer agree on a plan. Good communications. Faith and trust in an honest supplier. Good relations. Faith and trust in an honest supplier. Good relations. Proven history of quality with a stable and continuous process. Proven history of quality with a stable and continuous process. Clear criteria for action plan. Clear criteria for action plan.

Discussion Topics Compendial requirements Compendial requirements Regulatory expectations Regulatory expectations Current state, pro/con/concerns Current state, pro/con/concerns Desired state for excipients Desired state for excipients Fraud, counterfeiting, adulteration Fraud, counterfeiting, adulteration Processes “Out of control.” Processes “Out of control.” Changes without notification Changes without notification

References NIST NIST ASQ (1996). ANSI/ASQ S1, “Attribute Skip-Lot Sampling Program.” ASQ (1996). ANSI/ASQ S1, “Attribute Skip-Lot Sampling Program.” Schilling, E. (1982). Acceptance Sampling in Quality Control, New York, NY: Marcel Dekker, pp Schilling, E. (1982). Acceptance Sampling in Quality Control, New York, NY: Marcel Dekker, pp Juran, J. and Godfrey, A. (1999). Juran’s Quality Handbook, Fifth Edition, pp , 46-32, New York: McGraw Hill. Juran, J. and Godfrey, A. (1999). Juran’s Quality Handbook, Fifth Edition, pp , 46-32, New York: McGraw Hill.