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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.

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Continuous Flow Mfg Skip-Lot Sampling Closing Presentation

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Continuous Flow MfgSkip-Lot SamplingClosing Presentation

Topic A

Lynn Torbeck

Frank Gomez

Domenick Amato

Continuous flow manufacturing

Batches and lots


“Skip Test” vs. “Skip Lot”

Statistical Sampling Plans


Supplier Relationships


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 Mfg

Common in chemicals to campaign large batches

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 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.

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.


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.


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.

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”


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

Lot size

Sample size

Accept on zero

Reject on one defect or failure

Matches Z1.4 GL I sample sizes

Square root of (N) +1

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.


Pre delivery sampleVery little

Tail gate sampleVery little

Pull on siteCommon

Sampling Plans

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.

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.


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.


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

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.

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.


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.


Many companies are doing “skip test” procedures.

Did not find any practice that needs to be changed or modified.


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

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