Chapter 37: Sampling Processes

General Sampling Requirements

It is desirable to have written procedures for sampling that include the names of person(s) authorized to take samples, the methods and equipment to be used, the amounts to be taken, and any precautions to be observed to avoid contamination of the material or any deterioration in its quality. Documented sampling procedures and sampling plans approved by the quality unit for all materials should be in place.

The European Union (EU) and World Health Organization (WHO) both have good manufacturing practices (GMP) that further prescribe that the sampling procedures should contain the instructions for any required subdivision of the sample, the type of sample container to be used, whether it is for aseptic sampling or normal sampling, labeling, storage conditions, and instructions for cleaning and storage of sampling equipment. Samples should be representative of the material being sampled and should be taken in a manner that does not compromise the integrity of the sampled material or the sample.

Each container of starting materials should be sampled for identification testing unless supplier validation has been done to permit reduced testing. Such reduced testing is not permissible for parenteral product actives or for materials coming from a broker. Acceptable means of validating the supplier processes are listed in EU Annex 8 and WHO Section 17.15. This validation should take account of:

• Nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements of the pharmaceutical industry

• Quality assurance (QA) system of the manufacturer of the starting material

• Manufacturing conditions under which the starting material is produced and controlled

• Nature of the starting material and the medicinal products in which it will be used

WHO GMP Section 17.16 lists minimum information to be included on the supplier’s certificate of analysis (COA) as identification, name, and address of the issuing supplier, signature of the competent official and statement of his/her qualifications, name of the material tested, batch number of the material tested, specifications and methods used, test results obtained, and the date of testing.

Sampling Facilities, Utensils, and Equipment

The sampling facilities should meet the general requirements described in EU GMP Chapter 3 and WHO GMP Chapter 7 for cleanliness and dust control, and should not result in cross-contamination or sample confusion. The WHO guidance (WHO Guidelines for Sampling of Pharmaceutical Products and Related Materials) provides details on facilities and equipment to be used in sampling.

Sampling facilities should be designed to prevent contamination of the opened container, prevent cross-contamination by other materials, product, and the environment, and protect the individual who samples during the sampling procedure. Where possible, sampling should be performed in an area or booth designed for the purpose. The area in which the sample was taken should be recorded. Some materials should be sampled in special or dedicated environments (for example, aerosol valves, hormones, and penicillins).

Sample Containers and Labeling

Sample containers should not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the material being sampled, and should provide adequate protection from external factors in storage and use that can cause deterioration. Finally, sample containers should be clean and, where required, sterilized and pyrogen free.

Samples should be labeled to maintain traceability and identity. WHO Section 17.12 and EU GMP Section 6.13 specify label content for samples, with WHO being more prescriptive. Section 17.12 lists the following requirements for sample label content:

• Name of the sampled material

• Batch or lot number

• Number of the container from which the sample was taken

• Number of the sample

• Signature of the person who has taken the sample

• Date of sampling

Training of Personnel

Each GMP requires personnel to adequately train for the jobs they perform, including 21 CFR 211.25, EU GMP Chapter 2, and WHO GMP Section 10. EU GMP Annex 8 further specifies that personnel should receive initial and ongoing training in the disciplines relevant to correct sampling. The training should include sampling plans, written sampling procedures, techniques and equipment for sampling, information about the risks of cross-contamination, the precautions to be taken with regard to unstable and/or sterile substances, the importance of considering the visual appearance of materials, containers, and labels, and the importance of recording any unexpected or unusual circumstances.

Sampling of Starting Materials for API Manufacturing

At least one test to verify the identity of each batch of material should be conducted, with certain exceptions: processing hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s COA is obtained, showing that these raw materials conform to established specifications. Visual examination of containers and labels and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis. Sampling should be conducted at defined locations and following procedures designed to prevent contamination of the material sampled and contamination of other materials. Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

Sampling of Packaging Materials

EU GMP Annex 8 states that the sampling plan for packaging materials should take account of the quantity received, the quality required, the nature of the material (for example, primary packaging materials and/or printed packaging materials), the production methods, and what is known of the QA system of the packaging materials manufacturer based on audits. The number of samples taken should be determined statistically and specified in a sampling plan.

WHO guidance cautions against mixing of printed packaging materials. Only one material should be sampled at a time, and the WHO guidance explicitly states that samples of packaging materials should never be returned to the consignment. It considers sources of nonhomogeneity in packaging material batches and recommends that sampling take these potential sources of nonhomogeneity into account. The sources of nonhomogeneity include materials manufactured on different days or machines, materials manufactured on one machine but at different stations (for example, molding stations), packaging manufactured with different source materials, and change in quality during the process (for example, container wall thickness and text legibility).