Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay?

Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay?

Maybe. It depends on the cause and consistency of the reject rate. Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes. This should not of itself be a concern. The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling. This is most pronounced for processes involving lamination of rolls of various component layers. Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream.

We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch. Waste in excess of the normal operating rates may need (see 21 CFR 21.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects...or both) and the consequences on product quality assessed. We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.


  • 21 CFR 211.100: Written procedures; deviations
  • 21 CFR 211.103: Calculation of yield
  • 21 CFR 211.110: Sampling and testing of in-process materials and drug products
  • 21 CFR 211.192: Production record review

211.100 Written procedures; deviations.

(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. 

(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

211.103 Calculation of yield.

Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall either be performed by one person and independently verified by a second person, or, if the yield is calculated by automated equipment under § 211.68, be independently verified by one person.

211.110 Sampling and testing of in-process materials and drug products.

(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate: 

(1) Tablet or capsule weight variation; 

(2) Disintegration time; 

(3) Adequacy of mixing to assure uniformity and homogeneity; 

(4) Dissolution time and rate; 

(5) Clarity, completeness, or pH of solutions. 

(6) Bioburden testing. 

(b) Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples shall assure that the drug product and in-process material conform to specifications. 

(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods. 

(d) Rejected in-process materials shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

211.192 Production record review.

All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.

*Source: FDA website

Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay?

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