Sampling and Testing in Exhibit and Process Validation Batches : Pharmaceutical Guidelines

Sampling and Testing in Exhibit and Process Validation Batches

Purpose of sampling, sampling area, sampling records, and procedure of sampling including 3x sampling process validation.
Sample is a portion of a material collected according to a defined sampling procedure. The size of any sample should be sufficient to allow all anticipated test procedures to be carried out, including all repetitions and retention samples.
Purpose of Sampling:
Sampling Procedure
Sampling may be required for different purposes, such as pre-qualification, acceptance of consignments, batch release testing, in-process control, special controls, inspection for customs clearance, deterioration or adulteration, or for obtaining a retention sample. The tests to be applied to the sample may include:
— Verifying the identity;
— Performing complete pharmacopoeia or analogous testing; and
— Performing special or specific tests.
The materials to be sampled belong to the following classes:
— Starting materials for use in the manufacture of finished pharmaceutical products;
— Intermediates in the manufacturing process (e.g. bulk granule);
— Pharmaceutical products (in-process as well as before and after packaging);
— Primary and secondary packaging materials; and
— Cleaning and sanitizing agents, compressed gases and other processing agents.
Sampling facilities should be designed to:
— Prevent contamination of the opened container, the materials and the operator;
— Prevent cross-contamination by other materials, products and the environment; and
— Protect the individual who samples (sampler) during the sampling procedure.

Where possible, perform sampling in an area or booth designed for and dedicated to this purpose, although this will not be possible where samples are required to be taken from a production line (e.g. in-process control samples). Record the area in sampling record in which the sample was taken and keep a sequential log of all materials sampled in each area. Sampling from large containers of starting material or bulk products can present difficulties. Whenever possible, carry this work in a separate, closed cubicle within the warehouse, to reduce the risk of contamination (e.g. by dust) of either the sample or the materials remaining in the container, or of cross-contamination. Some materials should be sampled in special or dedicated environments (e.g. when sampling articles for which contamination with dirt or particles from the environment should be avoided, such as aerosol valves, hormones and penicillin).

To perform the sampling operation, adequate training to the person in the practical aspects of sampling and to execute the work effectively and safely sufficient knowledge of pharmaceutical substances should be given. It is important that personnel carrying out the sampling should be suitably trained in the techniques and procedures used. Document the training in the individual’s training records. Clearly record sampling dates in the sampling records, the sampled container and the identity of the person who sampled the batch. A conscientious approach, with meticulous attention to detail and cleanliness is essential.  Remain alert to any signs of contamination, deterioration or tampering. In detail record any suspicious signs in the sampling record. If a governmental agency needs a sample of a sterile or bulk pharmaceutical product manufacturer’s personnel will collect the sample, using their own procedures. Before sampling the material read the relevant health and safety information e.g. material safety data sheet (MSDS) for a pharmaceutical product and related materials. Keep in mind necessary safety precautions and requirements for both the operator and the environment. Wear appropriate protective clothing for the task. If specific safety precautions are required, such as the use of respiratory equipment, give proper training for its use and operation. 
Keep a safe access to the place where the sample is taken, and the places where the samples are taken for storage. The sample storage areas should have adequate light and ventilation and should be arranged to satisfy the requirements for safety as well as any special ones arising from the characteristics of the material being sampled. Care should be taken to guard against collapse of stacked containers or solids in bulk. Keep all the tools needed to open the containers (e.g. packages, barrels and others). Tools may include knives, pliers, saws, hammers, wrenches, implements to remove dust (preferably a vacuum cleaner), and material to reclose the packages (such as sealing tape), as well as self-adhesive labels to indicate that some of the contents have been removed from a package or container.  
For liquids use pipettes fitted with suction bulbs, cups or beakers, dippers and use funnels for liquids of low viscosity. The use of glass should be avoided for sampling of highly viscous liquid. 
A suitable inert rod can be used for highly viscous liquid, and spatulas or scoops are needed for powdered and granular solids. Sterile pharmaceutical products should be sampled under aseptic conditions, and only when deemed absolutely essential. All sampling tools and implements should be made of inert materials and kept scrupulously clean. After use or before reuse, wash thoroughly rinse with water or suitable solvent and dry. Store in clean conditions. Adequate washing facilities should be provided in the sampling area. Document and record the cleaning procedure used for all sampling tools and implements.

Related: Procedure for Sampling in Process Validation

Sampling and Testing the Powder Mix of Exhibit and Process Validation Batches:
Carefully identify at least 10 sampling locations in the blender to represent potential areas of poor blending. For example, in tumbling blenders (such as V-blenders, double cones, or drum mixers), select samples from at least two depths along the axis of the blender. For convective blenders (such as a ribbon blender), made a special effort to implement uniform volumetric sampling to include the corners and discharge area (at least 20 locations to adequately validate convective blenders). Collect at least 3 replicate samples from each location. This triplicate sampling is called 3x sampling. First sample is used for analysis, second for repeat analysis and third is retained as control sample. Samples should meet the following criteria:
Assay one sample per location (number of samples 20 for ribbon blender).
RSD (relative standard deviation) of all individual results should be 5.0 percent.
All individual results should be within 10.0 percent (absolute) of the mean of the results. If samples do not meet these criteria, investigate the failure. Do not proceed any further until the criteria are met.

In-Process Dosage Unit Sampling and Analysis for Exhibit and Process Validation Batches:
Carefully identify locations throughout the compression or filling operation to sample in process dosage units. For sampling locations include significant process events such as hopper changeover, filling or machine shutdown and the beginning and end of the compression or filling operation. Sample 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 sampling data to demonstrate that the batch has a normal distribution of active ingredient. Investigate indications of trends, bimodal distributions, or other forms of a distribution other than normal.
Prepare a summary of this analysis. Include potential investigation results along with a description of batch normality in the summary.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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