Process of Sampling and Sample Management in the Pharmaceutical Industry

Sampling and sample management are central elements of quality assurance in the pharmaceutical industry. They form the foundation of every analytical test and, consequently, of every batch release decision. Errors in sampling may result in analytically correct results that are nevertheless not representative of the entire batch, with potentially serious consequences for product quality, patient safety, and regulatory compliance.

Incorrect sampling renders even the best analytical method meaningless. Accordingly, a clearly defined, validated, and documented sampling process is of critical importance.

Regulatory Framework

At the European level, numerous - more or less specific - requirements for sampling arise from the various GMP regulations, in particular from the EU GMP Guide.

Sampling is described in more detail in Chapter 6.11 to 6.14 of EU GMP Guide Part I:

• "The sample taking should be done and recorded in accordance with approved written procedures [...]"

Chapter 6.11 specifies, among other things, predefined elements such as the sampling method, the amount of sample to be taken, and instructions for cleaning and storing sampling equipment.

• "6.12 Samples should be representative of the batch of materials or products from which they are taken. Other samples may also be
  taken to monitor the most stressed part of a process (e.g. beginning or end of a process). The sampling plan used should be appropriately justified and based on a risk management approach."
• "6.13 Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from
  which samples have been drawn. They should be managed in a manner to minimize the risk of mix-up and to protect the samples from adverse storage conditions."

Chapter 6.14 refers to Annex 19 of the EU GMP Guide.

Further requirements relating to sampling are found in other sections of EU GMP Guide Part I. According to Chapter 3.22, sampling of starting materials should normally be performed in a separate area. If carried out in the storage area, appropriate measures must be taken to prevent contamination or cross-contamination.

In addition, Chapters 4.14 and 4.16 require specifications that include sampling instructions. Chapter 4.25 requires written procedures describing, among other things, sampling methods, equipment to be used, the amounts to be taken, and all necessary precautions to prevent contamination or deterioration in quality. These procedures must be available to the Quality Control Department (Chapter 6.7).

Annex 8 of the EU GMP Guide provides additional guidance on sampling of starting and packaging materials and defines requirements for sampling personnel.

The fundamental requirements for sampling applicable to API manufacturers are largely analogous to those for finished product manufacturers. Relevant provisions are found in particular in Chapter 7.3 (Sampling and Testing of Incoming Production Materials), Chapter 8.3 (In-process Sampling and Controls), and Chapter 11.7 (Reserve/Retention Samples) of EU GMP Guide Part II.

National and International Requirements

In addition to supranational frameworks such as EU GMP or other regional GMP systems, applicable national legislation and implementing regulations must always be considered. While GMP guidelines provide the overarching principles for sampling and sample management, national laws may contain additional binding requirements regarding responsibilities, documentation, testing obligations, and release decisions. Manufacturers are therefore required to ensure compliance not only with international GMP standards but also with the specific legal framework of the country in which they operate.

Germany serves as one example: In Germany, the Medicinal Products and Active Pharmaceutical Ingredients Manufacturing Ordinance (Arzneimittel- und Wirkstoffherstellungsverordnung - AMWHV) must additionally be considered. Section 14(1) AMWHV requires the testing of starting materials, finished products, and, where appropriate, intermediates as well as containers, packaging and labelling materials in accordance with approved test instructions. Under Section 12(1) AMWHV, the Head of Quality Control is responsible, in particular, for approving specifications, sampling instructions, and test instructions, and for deciding on the release or rejection of materials.

In the United States, relevant requirements are primarily defined in 21 CFR Part 211 (Subparts E and I). Here as well, sampling must reliably reflect the quality of the entire batch. Deficiencies in sampling are regularly classified by the FDA as critical GMP deviations.

Fundamental GMP Principles of Sampling

Regardless of product type or manufacturing stage, the following core principles apply:

• Representativeness of the sample
• Protection of the sample from contamination, mix-up, or alteration
• Protection of the product from contamination
• Clear traceability to the batch
• Complete documentation

These principles must be ensured for starting materials, intermediates, bulk product, and finished products alike.

Practical Implementation of Sampling

The first step is to define a sampling strategy specifying:

• Which materials are subject to sampling
• When sampling takes place
• The number of sample increments or units to be taken
• Whether individual samples or composite samples are used
• Which samples are designated as retention samples

The sampling strategy should be risk-based and aligned with product, process, and material characteristics.

Sampling must be based on approved SOPs and/or sampling protocols. These include, among other elements:

• A detailed description of the sampling procedure
• Required equipment and tools
• Hygiene requirements
• Sample labelling instructions
• Measures in case of deviations

Unclear or overly generic procedures are a frequent cause of inspection findings.

In addition, qualification of sampling equipment and containers is necessary. Sampling equipment and containers must:

• Be suitable for their intended purpose
• Be appropriately cleaned and, if necessary, sterilised
• Be designed to prevent interaction with the product

For reusable equipment, cleaning procedures must be defined and validated.

Sampling may only be performed by trained and authorised personnel. It must be ensured that:

• The material is uniquely identified
• No contamination of the product occurs
• The sample is correctly taken, closed, and labelled
• Deviations are documented immediately

Specific measures may be required depending on the material type (e.g. powders, liquids, sterile products).

Labelling is also a critical element of sample management. Each sample must be clearly identified, for example with:

• Material or product name
• Batch number
• Date of sampling
• Name of the sampler
• Type of sample (e.g. test sample, retention sample)

Sampling activities must be fully documented in a sampling record or within validated electronic systems.

Concerning storage and transport, the following applies: After sampling, samples must:

• Be stored under defined conditions
• Be protected from light, moisture, and temperature deviations
• Be transferred to the QC laboratory without undue delay

Sample transport is subject to GMP requirements as part of sample management.

Retention samples are a mandatory element of GMP. They allow retrospective evaluation of batch quality after market release, for example in the case of complaints or recalls.

• Requirements include:
• Sufficient quantity of the retention sample
• Storage under defined conditions
• Retention period in accordance with regulatory requirements
• Clear identification and documentation

Typical Deficiencies in Sampling and Sample Management

Inspection findings frequently include:

• Missing or inadequate sampling strategies
• Non-representative samples
• Unclear responsibilities
• Insufficient personnel training
• Incomplete documentation
• Contamination risks during sampling

Such deficiencies may ultimately invalidate analytical results.

Practical Implementation

GMP-compliant sampling requires:

• Clearly defined processes and responsibilities
• Regular training
• Risk-based review of sampling strategies
• Integration into the pharmaceutical quality system
• Regular self-inspections

Sampling should not be regarded as a purely operational activity, but as a quality-critical process.

Recommendations for GMP Training on Sampling

Appropriate training topics include:

• GMP fundamentals of sampling and sample management
• Sampling plans and representativeness
• Hygiene and contamination prevention
• Documentation and data integrity
• Handling deviations during sampling

Targeted training significantly reduces errors and improves inspection readiness.

Further detailed information is available in the guidance document "Laboratory Data Management Guidance – Sampling and Sample Management“ published by the ECA Analytical Quality Control Group (AQCG). AQCG members also have access to a recording of the accompanying webinar. Membership in the AQCG is free of charge and can be applied for via the group’s website.