Questions and Answers on (Reduced) Sampling
Testing of active pharmaceutical ingredients (APIs), excipients, packaging materials, intermediates and finished products is one of the main tasks of the quality control unit in the pharmaceutical industry. During sampling, a small part of a batch or delivery is taken and analyzed. The results are then used to draw conclusions about the quality of the entire batch or delivery. Correct sampling plays a key role in this process. Any analytical method cannot compensate for errors that have occurred during sampling, no matter how good it may be.
Regulatory Requirements for Sampling
First of all, country-specific requirements may need to be considered. In Germany, for example, the Ordinance on the Manufacture of Medicinal Products and Active Pharmaceutical Ingredients (Arzneimittel- und Wirkstoffherstellungsverordnung (AMWHV)1 must be followed with regard to sampling. § 14 (1) AMWHV contains the general requirement to test starting materials and finished products, if applicable intermediate products and containers, outer packaging, packaging and labeling materials, and package inserts in accordance with test instructions. In this context, according to § 12 (1) AMWHV, the head of quality control has the task of approving the specifications, sampling plans and test instructions. He or she finally has to decide on the approval or rejection of starting materials, packaging materials and intermediate products.
The various GMP regulations, in particular the EU GMP Guidelines, provide a number of more or less specific requirements for sampling. Sampling is described in more detail in Chapters 6.11 to 6.14 of the EU GMP Guidelines Part I.2 The sample taking should be done and recorded in accordance with approved written procedures. Chapter 6.11 lists aspects that must be determined in advance for this purpose, such as the method of sampling, the amount of the sample to be taken, and instructions for the cleaning and storage of sampling equipment. According to Chapter 6.12, samples should be representative of the batch of materials or products from which they are taken. Furthermore, the sampling plan used should be appropriately justified and based on a risk management approach.
Chapter 6.13 provides instructions for labeling and handling of the sample containers and Chapter 6.14 contains a reference to Annex 19 of the EU GMP Guidelines.3
In addition, the EU GMP Guidelines Part I also contain other requirements for sampling. For example, according to Chapter 3.22, sampling of starting materials should normally be done in a separate area. If it is performed in the storage area, measures must be taken to prevent contamination or cross-contamination. Specifications must be available for both starting materials and primary or printed packaging materials (Chapter 4.14) and finished products (Chapter 4.16), including directions for sampling. According to Chapter 4.25, written procedures should be available that include methods of sampling and equipment to be used, the amounts of samples to be taken, and any precautions to be observed to avoid contamination of the material or any deterioration in its quality. These procedures must also be readily available to the quality control department, as can be seen in Chapter 6.7.
In addition, Annex 8 of the EU GMP Guidelines4 must be considered, which contains additional information on the sampling of starting and packaging materials as well as on the personnel who take samples.
The principle sampling requirements for API manufacturers are largely similar to those for pharmaceuticals. Provisions in this regard can be found in particular in Chapter 7.3 (Sampling and Testing of Incoming Production Materials), Chapter 8.3 (In-process Sampling and Control) and 11.7 (Reserve/Retention Samples) of the EU GMP Guidelines Part II.5
For the United States, the Code of Federal Regulations must be followed. Requirements for sampling can be found in 21 CFR 211 (Current Good Manufacturing Practice for Finished Pharmaceuticals), mainly in Subpart I (Laboratory Controls) and Subpart E (Control of Components and Drug Product Containers and Closures).
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Does the Sample Drawing have to be carried out by the Quality Unit?
CONCEPT HEIDELBERG and the ECA Academy regularly hold seminars dealing with different aspects of sampling. In one of these events, the question came up whether sampling must be carried out by quality control employees or if other persons, e.g. warehouse or production staff, may also draw the samples.
As shown above, the sampling requirements are described in the EU GMP Guidelines. Although the EU GMP Guideline Part I states that quality control is concerned with sampling (Chapter 6, Principle) and that quality control personnel should have access to the production areas for sampling (Chapter 6.4), there is no explicit requirement that the persons taking the samples have to belong to the quality control department. This requirement cannot be derived from the other passages of the EU GMP Guidelines either.
It is clear that the personnel must be trained and approved for sampling. This already follows from the general principles described in Chapter 2 of the EU GMP Guidelines Part I or Chapter 3 of the EU GMP Guidelines Part II, according to which personnel with the necessary qualifications and practical experience must be available for all GMP-relevant activities and should also receive continuing training. Chapter 1.9 of the EU GMP Guideline Part I further states: "Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by approved personnel and methods". Annex 8 of the EU GMP Guidelines additionally stipulates the following: "Personnel who take samples should receive initial and on-going regular training in the disciplines relevant to correct sampling."
As with Part I, Part II of the EU GMP Guidelines does not contain any specific statements on who exactly has to conduct the sampling. However, an interesting note can be found in the ICH Q7 guideline6 question and answer document.7 Number 2.4 deals with the question of whether ICH Q7 requires that sampling be performed by the quality unit. The answer to this question is a clear "no." In explaining the reasoning, it is stated that ICH Q7 does prescribe specifically who should perform the sampling. However, the quality unit is responsible for reviewing and approving sampling plans and procedures. Sampling should also be performed by appropriately trained personnel and appropriately documented.
The fact that the quality unit is responsible for reviewing and approving sampling plans and procedures is also a legal requirement for the United States. A provision stating this can be found in 21 CFR 211.160.
It can thus be summed up that it cannot be concluded from the GMP regulations that sampling must be performed by quality control staff. However, it is clearly specified that the employees concerned must be trained, that the sampling procedures must be approved by the quality control department, and that the overall responsibility also lies with the quality control department.
Under what Prerequisites is Reduced Sampling Acceptable?
Another topic repeatedly discussed in the CONCEPT HEIDELBERG and ECA Academy seminars is reduced sampling of starting materials.
Reduced sampling means that not all containers of a delivery or a batch are sampled, but only a previously specified number. This is to be distinguished from reduced testing, in which only individual pre-specified parameters of a specification are tested. In principle, both concepts can also be combined.
On the one hand, this article is intended to highlight the conditions under which reduced sampling is possible in principle. On the other hand, it will be discussed whether each individual container of a starting material must be sampled for identification purposes, or whether a random sample can also be sufficient in this respect.
For these questions, as with sampling in general, there may be country-specific laws. For Germany, the basic rules laid down in the AMWHV must first be noted. According to § 13 (3) AMWHV, only active ingredients and excipients that have been manufactured in accordance with GMP and whose quality has been determined and appropriately identified may be used as starting materials for the manufacture of medicinal products. Suppliers of starting materials and primary and secondary packaging materials used in the manufacture of medicinal products must, in accordance with § 11 (2) AMWHV, be qualified within the framework of the QM system of the processing plant in accordance with a procedure laid down in writing or electronically. For active ingredient suppliers, an on-site audit is even mandatory in line with § 11 (3) No. 1 AMWHV.
At the EU level, the following can be noted: In principle, according to Chapter 5.35 of the EU GMP Guidelines Part I, manufacturers of finished products are responsible for any testing of the starting material as described in the marketing authorisation dossier. They can utilise partial or full test results from the approved starting material manufacturer. In this case, however, at least identification testing of each batch according to Annex 8 is required. In addition, the requirements described in chapter 5.36 (audit performed, quality history, evaluation of the test results by comparison with the results of own full analyses, etc.) must be fulfilled. As a rule, at least three full analyses are expected before test results are used from the approved starting material manufacturer.
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How the identity of a batch of a starting material must be ensured is also described in Chapter 5 of the EU GMP Guidelines Part I. If one material delivery is made up of different batches, each batch must be considered individually, i.e. sampled, tested and released separately, in accordance with Chapter 5.31. According to Chapter 5.33, the identity of the contents of each container of starting material must be ensured.
According to Chapter 7.30 of the EU-GMP Guidelines Part II "at least one test to verify the identity of each batch of material should be conducted. […] Supplier's Certificate of Analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers". Chapter 7.31 says that "full analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis. Reliability of Certificates of Analysis should be checked at regular intervals." Chapter 7.32 contains an exception for processing aids, hazardous or highly toxic raw materials. These do not need to be tested, provided that the manufacturer's certificate of analysis is available and shows that they conform to the specification.
Annex 8 of the EU GMP Guidelines formulates the general expectation to take samples from all containers and to perform an identity test on each sample. However, it is expressly permissible "to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled."
Annex 8 also lists the aspects to be taken into account in such a validation. For example, the manufacturer of the starting material in question must have a functioning quality system and the manufacturing conditions under which the starting material is produced and controlled must be evaluated. Under these prerequisites, identity testing is possible on only part of the containers, provided that the starting materials comes from a single product manufacturer or plant, and also for starting materials coming directly from a manufacturer or in the manufacturer's sealed container. For the latter, a history of reliability and regular audits of the manufacturer's quality assurance system must be conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body. Conversely, in cases where starting materials are supplied by intermediaries and the source of manufacture is unknown or not audited, and in the case of starting materials for use in parenterals, it is considered unlikely that validation can succeed. In these cases, an identity check will therefore generally have to be carried out on a container-by-container basis.
With regard to the requirements applicable to the US, the following can be stated: 21 CFR Part 211.84 requires that sampling be based on statistical criteria and that each lot shall be withheld from use until it has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit. Part 211.84(b) requires that representative samples be taken from each shipment of a batch for testing or examination. The number of containers to be sampled and the amount of material to be taken from each container must be based on appropriate statistical criteria and should also take into account the supplier's quality history. Further information on the interpretation of the regulations can be found in a question and answer catalog published on the FDA website.8
About the Author:
Dr Markus Funk joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.
1 Verordnung über die Anwendung der Guten Herstellungspraxis bei der Herstellung von Arzneimitteln und Wirkstoffen und über die Anwendung der Guten fachlichen Praxis bei der Herstellung von Produkten menschlicher Herkunft (Arzneimittel- und Wirkstoffherstellungsverordnung - AMWHV).
2 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Part I - Basic Requirements for Medicinal Products.
3 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 19: Reference and Retention Samples.
4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 8: Sampling of Starting and Packaging Materials.
5 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use – Part II: Basic Requirements for Active Substances used as Starting Materials.
6 ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.
7 Q7 Q&As – Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (https://www.ich.org/page/quality-guidelines).
8 Questions and Answers on Current Good Manufacturing Practices—Control of Components and Drug Product Containers and Closures (https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-currentgood-manufacturing-practices-control-components-and-drug-product).