DATA INTEGRITY (ALCOA ++)

Stratified Sampling In-Process

 (Finished Dosage Units)

INTRODUCTION

This guidance is intended to assist manufacturers of human drug products in meeting the requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to ensure uniformity of in-process powder blends and finished dosage units. This guidance describes the procedures for assessing powder mix adequacy, correlating in-process dosage unit test results with powder mix test results, and establishing the initial criteria for control procedures used in routine manufacturing.

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

Scope

Stratified sampling is the process of sampling dosage units at predefined intervals and collecting representative samples from specifically targeted locations in the compression/filling operation that have the greatest potential to yield extreme highs and lows in test results.  These test results are used to monitor the manufacturing process output that is most responsible for causing finished product variability.  The test results can be used to develop a single control procedure to ensure adequate powder mix and uniform content in finished products.

The methods described in this guidance are not intended to be the only methods for meeting US-FDA requirements to demonstrate the adequacy of powder mix.  Traditional powder blend sampling and testing, in conjunction with testing for uniformity of content in the finished product, can be used to comply with current good manufacturing practice requirements

Stratified In-Process Dosage Unit Data

                                                                                                               

We recommend the following steps for correlation:

·         Conduct periodic sampling and testing of the in-process dosage units by sampling them at defined intervals and locations throughout the compression or filling process.  Use a minimum of 20 appropriately spaced in-process dosage unit sampling points.  There should be at least 7 samples taken from each of these locations for a total minimum of at least 140 samples. 

·         Take 7 samples from each additional location to further assess each significant event, such as filling or emptying of hoppers and IBCs, start and end of the compression or filling process and equipment shutdown.  This may be accomplished by using process development batches, validation batches, or by using routine manufacturing batches for approved products.

·         Significant events may also include observations or changes from one batch to another (e.g., batch scale-up and observations of undesirable trends in previous batch data).

·          Prepare a summary of the data and analysis used to correlate the stratified sampling locations with significant events in the blending process.  Compare the powder mix uniformity with the in-process dosage-unit data described above.

Investigate any discrepancies observed between powder mix and dosage-unit data and establish root causes.  At least one trouble-shooting guide is available that may be helpful with this task. Possible corrections may range from going back to formulation development to improve powder characteristics to process optimization.  Sampling problems may also be negated by use of alternate state-of-the-art methods of in situ real-time sampling and analysis.

In-Process Dosage Unit Sampling and Analysis

We recommend the following steps: 

·         Carefully identify locations throughout the compression or filling operation to sample in-process dosage units.  The sampling locations should also include significant process events such as hopper changeover, filling or machine shutdown and the beginning and end of the compression or filling operation. There should be at least 20 locations with 7 samples each for a minimum total of 140 samples.  These include periodic sampling locations and significant event locations.  

·         Sample at least 7 in-process dosage units from each sampling location.

·         Assay at least 3 of the 7 and weight correct each result. (The number of samples should be specified and justified for a given product and process.)

·         Conduct an analysis of the dosage unit stratified sampling data to demonstrate that the batch has a normal distribution of active ingredient.  Indications of trends, bimodal distributions, or other forms of a distribution other than normal should be investigated.  If these occurrences significantly affect your ability to ensure batch homogeneity, they should be corrected.

Prepare a summary of this analysis.  Potential investigation results along with a description of batch normality should be included in the summary.