Laboratory Handling Controls
All samples and reagents coming into the laboratory must be checked and logged in before use. Laboratory procedures should be in place so materials are consistently received.
INCOMING MATERIAL RECEIPT, INSPECTION, AND SAMPLING
Receiving personnel in the warehouse are responsible to verify that the material received matches the associated paperwork and is what was ordered. This check is typically done by reviewing what was received against what was ordered on the purchase order. Once material is received into the system, warehouse personnel move the appropriate number of containers (based on the predefined sampling plan) to the inspection area. The containers moved into the inspection area are selected randomly by the warehouse personnel.
The quality inspectors compare the name of the material and vendor/manufacturer’s lot number on the container label against the information on the paperwork, which provides documentation that the material was received from an approved vendor. The quality personnel verify the shipping container to ensure it is appropriate, which is required to ensure that the packaging configuration is appropriate for use in production, as well as confirmation that the material is stable in the specific container. If there are specific storage requirements, the quality inspector will ensure that all documentation is in order to ensure that the material had been stored appropriately during transit.
The quality inspector prepares a sample container with the appropriate identifying information, such as material name, batch number, and vendor batch number, if applicable. The person performing the sampling and the date sampled are recorded on the sample container. Proper labeling is a good manufacturing practices (GMP) requirement and helps avoid costly mistakes and rework. Typically, laboratory samples are given a unique sample identification number.
The quality inspector ensures that the container is clean and places the container in an appropriate sampling area. Depending on what is being sampled, the sampling area may be a room or tent with appropriate high-efficiency particulate air (HEPA) ventilation up to a class I clean room. Once the quality inspector has donned the appropriate personal protective gear, the sampling can occur. The tools used in sampling must be clean to prevent contamination. Disposable sampling tools are often used; the benefit ofthis approach is that it nearly eliminates the potential of contaminating the sample with an improperly cleaned sampling tool.
The quality inspector opens the appropriate number of containers and begins to sample from each drum. Depending on the testing requirements for the material, individual samples may be pulled from each container, or a smaller amount may be pulled from each container and combined to make a composite sample. A reserve sample is often pulled in conjunction with the laboratory sample. Upon completion of sampling, the sample is delivered to the laboratory for testing. The sample is logged into the laboratory system and is scheduled for testing.
SAMPLES FOR PRODUCTS MANUFACTURED IN-HOUSE
During the manufacturing process for a material, operations personnel remove a representative composite sample from the manufacturing line as designated in their batch record or associated paperwork. Depending on the nature of the material being manufactured, the sample may come from an in-process manufacturing step, completed semifinished good, or final packaged product.
The batch record, or associated paperwork, should detail how and when to pull the sample. The sample container is typically identified in these procedures. The operator should use the appropriate sampling method as defined in the written instructions. The sample container should be labeled with at least the product name, batch number, and sampled-by date. Depending on the nature of the sample, other pertinent identifying information may be included on the label. If the manufacturing of the batch occurs over several shifts, staff performing the sampling should initial and date their activities on the sample label. At the completion of the sampling, the sample is sent to the laboratory. The sample is logged into the laboratory system and is scheduled for testing.
Stability Samples
Depending on regulatory commitments as well as the nature of the product being manufactured, stability testing will vary. Once a packaging batch is identified for a stability study, operations personnel pull an adequate amount of packaged product throughout the packaging run to meet the study requirements. At the completion of the sampling, the samples are transported to the laboratory and placed under appropriate environmental stability testing conditions. At the appropriate intervals, a sample is pulled and scheduled for testing.
Reagents or Solutions
Proper control and identification of reagents and solutions in the laboratory ensures that the materials used in the analysis of products are appropriate. A material safety data
sheet (MSDS) should accompany each receipt of a reagent. The MSDS contains much of the information needed to ensure proper handling and use of the material, what to do in the event of a spill, and so on. Before the material is handled, the MSDS should be reviewed to ensure that appropriate precautions are taken. The containers must be inspected to ensure their integrity. If a seal is broken, the solution has been frozen, the container is leaking, or the labeling is inconsistent with what was ordered, the material should not be used. A label containing information (Figure 24.1) should be secured on each of the reagent or solution bottles. Often, reagents inventory is managed though a laboratory information management system (LIMS). If this is the case, the information listed on the label may be derived from the database by a bar code instead of being listed on the label.
The expiration date of the reagent should be readily apparent on the container. For commercially procured reagents, the manufacturer-assigned expiration date is often used. If no expiration date is available, and the material is stable, a company may have a procedure in place that would allow it to assign a predefined expiration period based on the date of receipt. Shorter expiration dates may be required if stability is an issue for the material. For example, solutions that are prone to microbial growth, such as high-performance liquid chromatograph (HPLC) water, an opened date and use-by date may be added to the container upon opening. Table 24.1 contains some typical expiry dating periods for common solutions.
Some reagents and solutions may be used past their expiration date if the material can be recertified or re-qualified. For example, it is common to re-standardize or recertify volumetric solution upon use or at monthly intervals. The current compendia (European Pharmacopeia [PhEur], Japanese Pharmacopeia [JP], and United States Pharmacopeia [USP]) typically define the process for re-standardizing the most commonly used volumetric solutions.
The preparation of all solutions prepared in the laboratory must be documented. The prepared solution should be identified with, at a minimum, the name/composition of the solution, concentration, storage, re-standardization date, expiration date, reference, and analyst/date.
STANDARDS
Laboratories use primary and secondary standards to determine material results and equipment calibration. A primary standard is purchased from an official source, such as USP, British Pharmacopeia (BP), or National Institute of Standards and Technology (NIST). If no official source of a standard exists, material can be thoroughly characterized to ensure its identity, strength, quality, purity, and potency. Secondary or in-house standards are raw materials that have been assayed against a primary standard. When standards are received into a laboratory, traceability must be established. Most laboratories will assign a unique standard number and complete corresponding paperwork indicating the standard’s name, lot number, purity, expiration date, and Analysts must verify they are not using expired standards. Based on the USP publication, most companies will establish a bimonthly review of their standards to ensure no expired ones are in the laboratory.
SAMPLE STORAGE
The storage of samples is extremely important to ensure the integrity of the material. Once sample containers are received into the laboratory, the containers should be stored in a centralized location until testing is started. Samples should have some form of unique identification to differentiate them from the other samples in the laboratory. Once testing has been started, procedures will dictate how samples are prepared and stored. For example, if a sample is light sensitive, amber glassware is used in the sample preparations. During method validation, solution stability is determined. Upon completion of testing, most laboratories require solutions to be retained, even if the solution has expired, until data review is complete. If there is a need for an investigation, the expired solutions may be used for information.
21 CFR 211.170 requires a reserve sample that is representative of the batch to be retained. The reserve sample consists of at least twice the quantity necessary to conduct all required testing. Reserve samples are typically pulled during inspection sampling and/or final packaging. The reserve samples are maintained at warehouse conditions and evaluated once a year for signs of deterioration. The finished product reserve samples are maintained for one year past their expiration date. The raw material reserve samples must be maintained one year past the expiration of the last finished product they were used in. Most pharmaceutical companies have finished products with a maximum of 36-month expiration dating; thus, they can assign a five-year expiration date to the raw material reserve sample, which ensures they will meet the CFR requirement.
REAGENTS OR SOLUTIONS
Chemicals, reagents, and solutions must be stored in the laboratory in a manner that considers safety, chemical integrity, and efficient management. Materials must be stored in tightly sealed and chemically resistant containers. Strong bases should not be stored in glass containers because the hydroxide will slowly react with the silica. Exposure of materials to heat or direct sunlight should be avoided. If a material is easily oxidized, it may be stored with a layer of nitrogen. Some companies store those chemicals in desiccators and flush with nitrogen. Materials requiring refrigeration or freezing should be stored as such. Chemically incompatible materials will be segregated according to their MSDS requirements. Acids and bases are not stored together.
STANDARDS
Standards are stored according to the label instruction Typically standard are maintained in desiccators until use. If drying is required before use, the analyst should take only the amount needed and dry in an appropriate container. Once dry, the analyst can store the dried standard in a desiccator until it is needed. Unless otherwise specified, standards are typically weighed and diluted within 24 hours of removal from the oven. After weighing, the remaining dried material is discarded. The appropriate storage of the standard solution should be outlined in the company’s method. During method validation, standard solution stability should be determined.