Sampling of pharmaceutical products

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Narmdeshwar Dev Mishra M.Pharm (Pharmaceutics) narmdeshwar25@rediffmail.com Mob. No.9039822909 Monika Bhairam M.Pharm (Pharmaceutics) monikab430@gmail.com Columbia Institute Of Pharmacy Raipur (C.G) Sampling of pharmaceutical products and related materials

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Sample are the unit that provide the experimental observations, such as tablet sampled for potency and defects. Sampling may be defined as the process of removing appropriate number of item from a population in order to make interferences to the entire population. Regulatory authorities (including inspectorates), quality control laboratories . Introduction

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Before sampling purpose of sampling? type of tests intended to be applied to the samples? type of products/materials to be sampled? are responsibilities of the samplers clear?

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Sampling process Preparation for sampling Sampling operation Sample storage and retention

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Sampling tools should be available to the sampler, e.g. to open containers (knives, hammers,...), material to re-close the packages (sealing tape), self-adhesive labels to indicate that some of the contents have been removed, etc... Sampling tools should be made of inert materials (e.g. polypropylene or stainless steel; avoid glass) and kept very clean . After use, thoroughly washed, rinsed with water or suitable solvent, dried and stored in clean conditions. Disposable sampling materials can also be used. Washing facilities should be located in, or close to, the sampling area. Cleaning procedure should be documented and validated. Sterile pharmaceutical products should be sampled under aseptic conditions. I - Preparation for sampling

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Examples of types of sampling tools Spatulas for solids Dip tubes for liquids Sample thieves for solid samples in deep containers Bag-sampling spears for taking samples from bags

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Written sampling procedure: operations to be performed on a defined material for a specific purpose, including health/safety aspects . Sampling plan : description of the location, number of units and/or quantity of material that should be collected, and associated acceptance criteria. Make sure that representative samples are taken in sufficient quantity. Representative sample: sample obtained according to a sampling procedure designed to ensure that the different parts of a batch or the different properties of a non-uniform material are proportionately represented. Samples should never be returned to the bulk. II - Sampling operation

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Sampling operations should be supervised and documented => sample collection form => always kept together with the collected sample. Sample collection form : written record of the sampling operations, containing: batch number, sampling date/place, reference to sampling protocol used, description of containers and materials sampled, possible abnormalities, any relevant observations, name/signature of the sampler. Store the sample in a properly labelled container : sample type, name of material, identification code, batch number, code, quantity, date of sampling, storage conditions, handling precautions, container number. II - Sampling operation (cont.)

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Example of sample collection form Page 1 Page 2

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Containers Containers used to store a sample should comply with the storage directions for the active pharmaceutical ingredient, excipient or drug product: should not interact with the sampled material. should not allow contamination. should protect the sample from light, air and moisture. should be sealed and adequately labelled. avoid mix-up when containers are opened (screw caps, separate lids). manipulations/unauthorised opening should be easy detectable. transported in such way as to avoid breakage. III – Sample storage and retention

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Rooms for sample storage Security and adequate storage conditions (light, ventilation, safety requirements, and any special requirements) should be ensured for the rooms in which samples are stored. Samples should be stored according to the storage conditions as specified for the respective API, excipient or drug product. Packaging materials similar to those in which the bulk is supplied should be used for long-term storage. III – Sample storage and retention (cont.)

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Examples of types of containers used to store samples of starting materials and bulk products Bag for storage of samples Screw-top containers

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Regulatory issues for sampling Drug quality surveillance programmes Inspections

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The extent of the routine surveillance programmes for drug quality, carried out by National Drug Regulatory Authorities will depend on: capacity of the national drug QC lab extent to which the quality of the product has been assessed prior to registration extent to which the requirements for GMP are implemented number of products imported from abroad The programme should include marketed products, whether registered for sale or prepared in pharmacies. Each product should be assessed regularly (every 2-3 years). Particular attention to products of prime importance to public health programmes or potentially dangerous, unstable or difficult to formulate properly. I - Drug quality surveillance programmes

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The responsible laboratory should prepare the sampling programme (if needed under the guidance of the drug regulatory authority) every year or half a year. Sampling programme: Lists the products to be sampled during a given period Specifies the sampling procedure Specifies the size of the samples to be collected (including retention sample) States to what extent each brand of a given product will be sampled States which local authority or inspector will be responsible for sampling Indicates to which laboratory each sample should be sent (if more than 1) I - Drug quality surveillance programmes (cont.)

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Inspectors may take samples from: retail or hospital pharmacies (including preparations manufactured in bulk in the premises) industry wholesalers In case of a complaint received about a product, the sample should include the original container and if possible 1 or 2 unopened containers with the same batch number. In case of deteriorated dosage forms, the sample should consist of one or more containers showing visual signs of deterioration. II - Inspection

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Sampling is required for acceptance Starting materials Intermediates in manufacturing and bulk products Finished products Packaging materials

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Uniform material: sample can be taken from any part. Non-uniform material: Special sampling tools are needed. Alternatively, if applicable, restore uniformity before sampling (e.g. stratified liquid may be stirred or a solid deposit in a liquid may be dissolved by gently warming and stirring) – validated method In these cases, in order to prepare representative samples. I – Sampling of starting materials

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Intermediates: liquids and semi-solid products; powdered solids or granulates; unit dosages forms in bulk (tablets, capsules). Pay attention to the segregation of bulk materials during transportation. These products may be assumed as uniform if the transportation process has been validated , AND: They are labelled with name of the manufacturer and a single batch number; They have been produced according to GMP; and They are supplied with a certificate, issued in the country of origin, according to the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce II - Sampling of i ntermediates in manufacturing and bulk products

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Uniformity : a single consignment* of a product from a single manufacturer and labelled with a single batch number may be assumed to be uniform . The minimum size of the samples to be taken is determined by the requirements of the analytical procedure used to test the product (tests of unit dosage forms for uniformity of weight, volume or content, or sterility tests can require a large number of samples). Sampling and testing may be adjusted according to the experience with the source of the product , e.g. manufacturer or supplier. *Consignment: quantity of a bulk starting material or drug product, made by one manufacturer or supplied by one agent, supplied at one time in response to a particular request (1 or more containers, 1 or more batches). III - Sampling of f inished products

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Pay attention to mixing up printed packaging materials during sampling only 1 material should be handled at a time. adequately protect and identify the sample. Samples of packaging materials should never be returned to the consignment. During sampling, primary packaging materials should be protected against environmental contamination (e.g. special measures when sampling parenteral ampoules). IV - Sampling of p ackaging materials

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A consignment of packaging materials may NOT be considered homogeneous if: Materials manufactured on different days or machines Materials manufactured on one machine, but different stations (e.g. printing stations, moulding stations) Packaging manufactured with different source materials Change in quality during the process (colour variation, text legibility or change of printing plate, container-wall thickness...) Important to take random samples from across the consignment. Consider focus sampling based on the above mentioned risk factors. IV - Sampling of p ackaging materials (cont.)

Sampling Procedures:

Sampling Procedures Sampling plan for inspection by Attributes. Sampling plan for inspected by Variables. Attributes :- It refer to “go or no-go” situation in which item is examined or test to determine whether it conform to the rejection specification. It is based on the AQL (Acceptable quality limit). Variables :- It is based on the continuous distribution of measurement which measure degree of unacceptability between accepted and rejected situation.

Sampling methods:

Sampling methods Random sampling method :- According to W.M.Harper – “A random sample is a sample selected in such a way that every item in the population has an equal chance of being included.” Random sampling is based on the AQL value. The AQL inspection takes the samples from a goods, inspect them and depends on the quality of samples inspected and decide to accept or reject them.

Types of random sampling:

Types of random sampling Lottery method Random number Stratified sampling Systematic sampling Cluster sampling

Non-random sampling:

Non-random sampling Types :- It is Judgment, purposive or deliberate sampling. Convenience sampling Quota sampling

Sampling plans:

Sampling plans Single sampling plan Double sampling plan Multiple sampling plan Each sampling plan can be performed in three level :- normal, tightened and reduced, depending on quality of products. In industry, single and double normal sampling plans are applied.

Single sampling plan:

Single sampling plan Inspect a sample of “n” pieces from the lot “N”. If the number of defects found in sample does not exceed “c” ( accep . no.) the lot is accepted. If the number of defects found in sample exceed the value “c” all the pieces in the reminder of lot be inspected.

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Example Single Sampling Plan‐Normal Inspection • Assume AQL is 2.5% and lot size is 600 garments, find out the following : – The total number of samples need to inspect – The acceptable number of the samples – The rejection number of the samples

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Answer Single Sampling Plan S ample sizes of “80”. • So, 80 samples are needed to inspect out of 600 • At AQL 2.5%, if defective garments are less than or equal to 5, whole lots will be accepted, if it is found to be 6 or more, whole lots will be rejected.

Double sampling plan:

Double sampling plan In this sampling :- after test three condition arises….. Accept lot Reject lot No decision :- In this case second sample is taken and the to combine result of both the sample and made final decision.

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Example Double Sampling Plan Assume AQL is 4% and lot size is 2000 garments, find out from double sampling plan on the following: – The total sample sizes need to inspect – What is the first acceptable number – What is the second acceptable number

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Double Sampling Plan Sample size is 80. • First inspection, at AQL 4%, the acceptable number is 5, rejection number is 9 • If any number between 5 to 9, second inspection is needed. Answer For second inspection, the sample sizes again is 80 • At AQL 4%, the cumulated acceptable number is 12 and rejection number is 13. • Conclusion – If the number of defective garments found in the first sample is 6, and in second sample is 5, making a total of 11, then the whole lot of 2,000 pieces will be accepted.

Multiple sampling plan :

Multiple sampling plan In this sampling plan two sample are needed for the accept or reject the lot. Used for small sample size.

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Sampling plans is used for Starting materials Finished products Packaging materials

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“n- plan” “p- plan” “r-plan” Sampling plans for starting materials

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Only used when material is considered uniform and from a recognised source . I – The “ n- plan” N = sampling units in the consignment (e.g. individual package, drum or container) Calculate “ n ” ( n = units to be sampled). Select at random “ n ” units from N. Take a sample from these units. QC lab checks appearance + identity of each sample. If results concordant => combine samples into a single final sample. Take “analytical sample” for full testing. Keep the rest as “retention sample”. e.g. N =40 => n =7 (units to be sampled)

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NOTES: The “ n -plan” is NOT statistically based and should be used only as a guiding principle. The “ n -plan” is NOT recommended for use by control laboratories of manufacturers that are required to analyse and release or reject each received consignment of the starting materials used to produce a drug product.

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II – The “ p- plan” May be used when material is considered uniform , from a recognised source and the main purpose is to test for identity . Sample each of the N sampling units . QC lab checks appearance + identity of each sample. If results concordant => p final samples are formed by appropriate pooling. Keep the p samples for retention (or full testing if required). e.g. N =40 => p =3 (final samples after testing+pooling ) N = sampling units in the consignment (e.g. individual package, drum or container)

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III – The “ r- plan” May be used when material is considered non-u niform and/or obtained from a not well know source . Can be used for herbal medicinal products used as starting materials. Sample each of the N sampling units . QC lab checks appearance + identity of each sample. If results concordant => r samples are randomly selected. r samples individually fully tested . If results concordant => combine the r samples for the retention sample. e.g. N =40 => r =10 (randomly selected samples for testing) N = sampling units in the consignment (e.g. individual package, drum or container)

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THANK YOU