TASKS OF QUALITY CONTROL LAB. Eli.S M.Sc, Lect. No. 6

The Lab Quality System Organization Personnel Equipment Stock Management Quality Control Data Management Remind participants that site safety and waste management is one component of the lab quality system. SOPs, Documents & Records Occurrence Management Assessment (הערכה) Process Improvement Specimen Management Safety & Waste Management Eli.S M.Sc, Lect. No. 6

Out Of Specification (OOS) investigation QC WORK FLOW 4. Test samples Meet Specification YES NO 5. Review of batch record 7. Non conformance or Out Of Specification (OOS) investigation 6. Products release End Start 3. Sampling 2. Receiving 8. Products Reject Lab Records Release QC/QA Status Quarantine Reject Incoming materials Water Returned products Intermediates Bulks Finished products Environment monitoring Eli.S M.Sc, Lect. No. 6

CONTROL OF STARTING MATERIAL ACCEPTANCE All starting materials shall be verified prior to use. Verification should include the following: Review of Certificate of Analysis (COA) from the manufacturer versus approved specification Other tests may be conducted as appropriate: Identification test / package identification and other characteristic of the material shall be examined. Primary packaging: No leakage, sharp dents, tear , exposed parts and seal integrity. Legible label and identification and batch number Frequency: Every batch of manufacturer’s batch. Eli.S M.Sc, Lect. No. 6

RECEIPT There should be written procedure on the receiving, internal labeling, quarantine and storage of starting materials, packaging materials and other materials as appropriate. Upon receiving of the supplied goods, its identity, legibility((קריא of batch number, integrity of its primary packaging and seal shall be verified prior to acceptance. Eli.S M.Sc, Lect. No. 6

RECEIPT cont’ Certificate of Analysis (COA) shall be provided by the supplier accompanying the receiving of starting materials Quarantine goods shall be segregated from “Release” goods (YELLOW) Reject goods shall be stored in a define area with consideration of control access (e.g. Locked area )RED) Approved for use (GREEN) Eli.S M.Sc, Lect. No. 6

SAMPLING The sample taking shall be done in accordance with written procedure that describe: The method of sampling The sampling tools used The amount of samples to be taken The type and condition of the sample container to be used (i.e. amber glass bottle) Eli.S M.Sc, Lect. No. 6

SAMPLING Cont’ The identification of the container sampled Special precaution for hazardous materials The storage condition (if any) Instruction for cleaning and storage of sampling equipment Instruction for re-sealing the opened container Eli.S M.Sc, Lect. No. 6

SAMPLING TOOLS Dip tubes Spatula for liquids Spears for bag for solids Eli.S M.Sc, Lect. No. 6

SAMPLING PLAN Raw Material Sampling plan for raw material should be based on defined sampling standard, for example: the “n plan” is based on the formula n = 1+√N, where N is the number of sampling units in the delivery the “p plan” is based on the formula p = 0.4 √N, where N is the number of sampling unit; or the “r plan” on the formula r = 1.5√N . reduce sampling plan such as “p plan” shall be considered only when there is established confidence on the material’s uniformity. Eli.S M.Sc, Lect. No. 6

SAMPLING PLAN Cont’ Packaging materials and Finished Product Sampling plans for packaging materials should be based on defined sampling standards, for example: British Standard BS 6001-1 ISO 2859 ANSI/ASQCZ1.4-1993 (American National Standards Institution) MIL STD 105E (1989) 414 (1968)   Eli.S M.Sc, Lect. No. 6

E. Solomon M.Sc, I – The “n-plan” Only used when material is considered uniform and from a recognised source. N = sampling units in the consignment (e.g. individual package, container) n= 1+√N 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) 1+ √40 =1+6=7 Lect. No. 8

I – The “n-plan” Cont’ 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 delivery of the starting materials used to produce a drug product.

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. p = 0.4 √N N = sampling units in the delivery (e.g. individual package, container) 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) 0.4*6 ~ 3

III – The “r-plan” May be used when material is considered non-uniform and /or obtained from a not well known source. Can be used for herbal medicinal products used as starting materials. 1.5√N N = sampling units in the delivery (e.g. individual package, container) 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)

I - Preparation for Sampling Sampling tools should be available to the sampler, e.g. to open containers (knives, hammers,...), material to reclose 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.

I - Preparation for Sampling Cont’ 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 (= demonstrated efficiency). Sterile pharmaceutical products should be sampled under aseptic conditions. Eli.S M.Sc, Lect. No. 6

II – Sampling Operation Written sampling procedure: operations to be performed on a defined material for a specific purpose, including health/safety aspects (see Appendix 3 of WHO guideline: Examples of steps to be considered for inclusion in a SOP). Sampling plan: description of the location, number of units and/or quantity of material that should be collected, and associated acceptance criteria.

II – Sampling Operation (cont’) 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. Eli.S M.Sc, Lect. No. 6

II – Sampling Operation (cont’) 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. Eli.S M.Sc, Lect. No. 6

Example of sample collection form (Appendix 2 of WHO guideline) Page 2 Page 1

II – Sampling Operation (cont’) Pay attention to any signs of non-uniformity of the material: Differences in shape, size, colour of particles in crystalline /granular / powdered substances. Moist crusts on hygroscopic substances. Solid deposits in liquids or semi-liquids. Stratification of liquids. In this case, sample portions of the material and test them separately from the material with normal aspect. Take into account previous experience with the product and supplier.

Sample Storage (Cont’) III – III – Sample SSSSS and retention Sample Storage (Cont’) III – 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.

III – Sample Storage (cont’) 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. Eli.S M.Sc, Lect. No. 6

III – Sample Storage and Retention (cont’) 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.

Bag for storage of samples Examples of types of containers used to store samples of starting materials and bulk products (Appendix 4 of WHO guideline) Bag for storage of samples Screw-top containers http://apps.who.int/prequal/info_general/documents/TRS929/WHO_TRS_929-Annex4.pdf

RETAIN SAMPLE Retain sample should be representative of the batch of materials or products from which they are taken Retain sample shall be of a size sufficient to permit at least 2 full re-examinations Eli.S M.Sc, Lect. No. 6

Reference RefR enR WHO guidelines for sampling of pharmaceutical products and related materials. Annex 4 of WHO Technical Report Series No. 929 (2005). ISO 2859 - Sampling procedures for inspection by attributes. British Standard BS 6001-1 - Sampling procedures for inspection by attributes. ISO 10725:2000 - Acceptance sampling plans and procedures for the inspection of bulk materials. Good Manufacturing Practices; Part I - Basic Requirements for Medicinal Products ; Part II - Basic Requirements for Active Substances used as Starting Materials. European Pharmacopoeia. Chapter 2.8.20. Herbal drugs: sampling and sample preparation. ANSI/ASQ Z1.4-2008 Standard (American National Standards Institute/American Society for Quality) - Sampling Procedures and Tables for Inspection by Attributes.