Transcript Continuous Flow Mfg Skip-Lot Sampling Closing Presentation
Continuous Flow Mfg Skip-Lot Sampling Closing Presentation
Topic A Lynn Torbeck Frank Gomez Domenick Amato
Overview
Continuous flow manufacturing Batches and lots Suppliers “Skip Test” vs. “Skip Lot” Statistical Sampling Plans USP Supplier Relationships
Continuous Flow Mfg
Defining Continuous Process: • Long term vs. short term • The size of the material exceeds the capacity of the equipment • The reactor full vs. ongoing production • Discrete activity
Continuous Flow
Common in chemicals to campaign large batches Sampling and testing procedures may help define a continuous vs. batch process.
Batches and Lots
210.3(b)(2) See definition of a batch • Discrete volume vs. ongoing production See definition of a lot • Lot is equal to a batch • Or, lot is a sub portion of a batch
Batches and Lots
Within the context of the GMP’s a batch or lot can be defined as part of the quality agreement between the supplier and customer The batch must have uniform characteristics regardless of contract.
Batches and Lots
A change in the manufacturing, a process upset, may cause a change in the definition of the batch size.
A batch can be defined by a predetermined interval, i.e. 6 hrs.
Drug manufacturer is responsible for assuring compliance.
Suppliers
Excipient suppliers are not generally qualified, but the Excipient manufacturers are qualified/ certified.
Need to know the supply chain including shipping and distribution.
Audit the excipient manufacturer for compliance.
Suppliers
Depending on the number of lots purchased choose an interval for certifying the reliability of excipient manufacturer’s C of A Interval of • 1, 3 times/yr • Test ten then every tenth lot or one per yr.
Drug manufacturer must test critical performance criteria. It may or may not be on the C of A.
Critical Excipients
Drug manufacturer determines what are critical excipients.
The extent to which GMP’s controls are applied depend on criticality and usage or intended use as determined by the drug manufacturer.
Defining a Batch
Different drug manufacturer have different acceptance criteria for raw material delivery and batch definition.
For some every shipment is a different batch, test all characteristics.
“Skip Testing”
Other companies do an ID test and accept other tests from the CoA of the previous shipments of the same supplier batch.
Quality history should not be used to sunset testing of critical attributes
Sampling Plans
Sampling • Variables with a spec range • Little or no attribute testing • Z1.4 and Z1.9, S1 are not used.
Square root of (N) +1 is used • Composite testing for variables test • Individual samples for ID but not for variables test All specification testing must be done.
Square root of (N) +1
Can be a valid sampling plan Lot size Sample size Accept on zero Reject on one defect or failure Matches Z1.4 GL I sample sizes
Sampling Plans
In practice, testing is accept on zero and reject on one.
Statistical “Skip Lot” testing is not being done because an ID must be done on all batches. Other tests may not be done as the supplier is doing the tests, “skip testing.”
Sampling Plans
If the supplier doesn't do the specification tests then the drug manufacturer must do the test.
Sampling • Pre delivery sample Very little • Tail gate sampleVery little • Pull on site Common
Skip Testing
API, 10 lots initial, then one a year Excipients, 5 lots initial then one a year A few companies use statistics to determine the skip testing.
Trending
Some companies are using control charts and process capability, Cpk, to monitor and trend data collected.
Some suppliers allow the customers to see the control charts.
USP
The USP can change the monograph given adequate scientific justification. The drug manufacturer may have to change the filing.
Time span for a change is 9-24 months.
Committees are volunteers.
Changes to Methods
Change to a non monograph method may require an update of the drug master file.
If a customer makes a change to a test for a critical parameter they may have to update the drug filing.
Supplier Relationships
Need a strong trusting relationship between supplier and customer.
Supplier relationship is critical for supplier certification.
Excipient manufacturer notifies customer of changes.
ISO document has criteria for supplier grades, A, B, and C.
Critical Quality Attributes
If a drug mfg identifies a critical quality attribute that is not a USP test then the mfg must develop a test.
Look at ICH and FDA guidances to determine what are the critical attributes, and FDA SUPAC guidances to determine the levels of changes stated therein.
Conclusion
Continuous flow processes can meet the GMP definitions of batches and lots.
Within the GMPs for continuous flow processes, a batch or lot can be defined by an agreement between the supplier or manufacturer and customer.
Conclusions
Square root of (N)+1 is being used correctly for composite samples.
Square root of (N)+1 can be a valid sampling plan.
Statistical Skip Lot testing can not be used since each lot must at least be tested for ID.
Conclusions
Many companies are doing “skip test” procedures.
Did not find any practice that needs to be changed or modified.
Closing Questions / Comments
Confusion exists because most excipient manufacturers do not conduct all tests because of their controls. If they do not run the test it must be clearly indicated since some one will need to run that test. (21 CFR 211.84) In today’s environment of PAT do all tests really need to be run if excipient manufacturers have the systems under control. (21 CFR 211.84) Does 21 CFR 211.84 need to be revised to allow for PAT?