Continuous Flow Mfg Skip-Lot Sampling Closing Presentation. Topic A Lynn Torbeck Frank Gomez Domenick Amato. Continuous flow manufacturing Batches and lots Suppliers “Skip Test” vs. “Skip Lot” Statistical Sampling Plans USP Supplier Relationships. Overview.
Batches and lots
“Skip Test” vs. “Skip Lot”
Statistical Sampling Plans
Long term vs. short term
The size of the material exceeds the capacity of the equipment
The reactor full vs. ongoing production
Discrete activityContinuous Flow Mfg
Sampling and testing procedures may help define a continuous vs. batch process.Continuous Flow
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 batchBatches 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.Batches and Lots
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
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.Suppliers
Drug manufacturer determines what are critical excipients. for certifying the reliability of excipient manufacturer’s C of A
The extent to which GMP’s controls are applied depend on criticality and usage or intended use as determined by the drug manufacturer.Critical Excipients
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.Defining a Batch
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“Skip Testing”
Sampling the CoA of the previous shipments of the same supplier batch.
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.Sampling Plans
Can be a valid sampling plan the CoA of the previous shipments of the same supplier batch.
Accept on zero
Reject on one defect or failure
Matches Z1.4 GL I sample sizesSquare root of (N) +1
In practice, testing is accept on zero and reject on one. the CoA of the previous shipments of the same supplier batch.
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.
Pre delivery sample Very little
Tail gate sample Very little
Pull on site CommonSampling Plans
API, 10 lots initial, then one a year drug manufacturer must do the test.
Excipients, 5 lots initial then one a year
A few companies use statistics to determine the skip testing.Skip Testing
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.Trending
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.USP
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.Changes to Methods
Supplier relationship is critical for supplier certification.
Excipient manufacturer notifies customer of changes.
ISO document has criteria for supplier grades, A, B, and C.Supplier Relationships
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.Critical Quality Attributes
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.Conclusion
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
Did not find any practice that needs to be changed or modified.Conclusions
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?Closing Questions / Comments