Control of Starting Materials in Good Manufacturing Practice

The independent quality control over starting materials is a critical step of manufacture is a basic GMP requirement. Since quality commences with the quality of materials. it’s important to verify that starting materials meet specifications before use. This is not after use. This is even more important for a new vendor, since there is no history of supply. The laboratory has a change of government approved tests that verify the identity, potency, purity and quality of the raw material. While the Certificate is helpful, it does not substitute for actual sampling and testing. GMP specifically only authorizes the Quality Unit to decide on the release or rejection of materials, Purchasing, IT, and Warehousing do not have this authority.  The final product is only as good as the starting materials used. To ensure the purity, identity, effectiveness and solely of finished products:

• Materials must be purchased only from approved suppliers to written specifications.
• All incoming materials must be inspected and/or tested to verify their suitability for use.
• Label all materials clearly to indicate their inspection and lest status.
• Materials must be stored safely to protect from deterioration and damage.
• Records must be maintained for all issued material in order to ensure traceability.

Receiving and Issuing Raw Materials One of the most important aspects of GMP is to ensure that the right raw materials are received and that the correct raw material batch is issued to production to commence manufacture. Mistakes in this activity can have significant consequences for patient safety, or cause batches to be rejected. Therefore, the utmost care must be taken when receiving, logging in, storing, and issuing of raw materials – Receiving GMP commences on receipt of the raw materials from the supplier. Raw materials must be checked that they are intact have been provided according to the paperwork and that labels identifying name batch number and expiry dole ore present. – Sampling and testing Laboratory sampling and testing confirm that the raw material received meets the company specifications for quality. There are specific GMP procedures for sampling of raw materials to protect the sampler and to protect the batch from environmental contamination. – Status Labelling On initial receipt, raw materials should be labelled “Hold” or “Quarantine”, and once they have passed QC testing, raw materials should be re-labelled “Released” or “Rejected”. It is important that the storage location matches the status of the raw material. GMP requires that only “Released” raw materials may be used in production. – Storage When raw materials are stored, they may deteriorate if they are exposed to elevated temperatures, moisture or are stored directly on the floor, or are in contact with walls. GMP requires that only authorised personnel are allowed to remove raw materials from storage. – Issue Raw materials are issue against documentation or requisitions provided by the company. GMP requires that all issues of raw material are accompanied by the correct paperwork, so that there is no potential for mix-up. Incorrect selection of a raw material may result in significant problems in manufacture or put the patient at risk. Receiving Materials Direct control over product quality begins when the starting materials first arrive at the inward goods receiving bay. There are a number of GMP controls that need to be put in place. These include:

• Checking that the identification is exactly the same on the container as it is on the paperwork
• Examining each container and verifying that containers are sealed, undamaged and clean
• Reporting raw materials when the contents are exposed
• Raising a non-conformance notice before accepting the material if any problems arise

Approving Suppliers  For a company to approve a supplier, a combination is needed of the following:

• Supplier audit
• Number of acceptable consecutive deliveries
• Verification of test results
• Supplier audit
• Number of acceptable consecutive deliveries
• Verification of test results
• Supplier questionnaire
• On-time delivery and other commercial issues
• Authenticity of Certificate of Analysis verified (lot number, signatory, company, results are in specification, etc.)

Issues When Receiving Material Chemical names Many raw materials have similar and sometimes confusing names. For example, “Ergotamine” can be confused with “Ergometrine”, which are two very different drugs. Similarly, the same item can be called by different names by different suppliers, for example, “sodium chloride” can be called “sodium soil”. Pay particular attention to the names of the material being delivered. Sometimes a supplier can mix up a delivery and send the wrong raw material with the right purchase order. Always double-check the name of the product needed against the paperwork of the supplier. Standard Names Register GMP rule requires companies to have a Standard Names Register matched too unique standard company item code. The purpose of this is to ensure that everyone in production uses the same terminology to avoid confusion. These names and codes should match the Master Bill of Materials. When labelling starting materials, always use the company standard name and matching code. Approved supplier The purchasing department usually only purchases from QA-approved suppliers, but occasionally there may be a mix-up. Always double-check the supplier origin lo make sure that the supplier is on the approved supplier list before accepting the delivery. Grade of material The purchasing department only purchases QA approved grades of chemicals, such as USP, BP or EP grades. The grade should be printed on the supplier label next to the name. Double-check the grade against the purchase order and supplier paperwork: before accepting the lot. Multiple lots on one delivery pallet Sometimes, different lots of some material or different materials arrive on some suppliers pallet. Often, the outer containers look alike as well. This can be confusing. Always double-c heck each container, and physically separate them from other lots, even of some material on receipt. Make sure that different lots are not mixed up, because it is unlikely that this problem will be picked up later in production. Storing Received Materials After receiving the material there are some essential GMP tasks that should be undertaken before storage:

• Remove the supplier’s status labels
• Apply the company’s identification and status labels
• Record the receipt of goods on company documentation
• Quarantine materials immediately after they have been accepted
• Check and process goods as soon as possible to help prevent material mix-ups and damage

Sampling and Testing of Materials Starting materials are sampled and tested to verily their quality. To ensure that the results are accurate and reliable:

• Follow exactly the written procedures for sampling to ensure that the sample represents the container it was taken from.
• Take samples in a separate area to prevent contamination.
• Test according to the methods detailed or referenced in the specifications

Sampling techniques 

1. The sampler wears glove to protect both the person and the chemical from being cross-contaminated.

2. The sampler is gowned to protect the chemical from contamination.

3. The sampling spoon is clean and inert to the chemical.

4. The chemical container is lined with plastic to protect the chemical from the outer cardboard.

5. The sample jar is amber to protect the chemical from light.

6. The sample jar is labelled on the body, not on the lid.

Important Aspects of Sampling

• Always use clean equipment, and inspect cleanliness prior to use.
• Always sample in a clean environment with air protection to prevent cross-contamination.
• Always sample wearing personal protection, including hat, gloves, coats, and where required, a mask.
• Always refer to specific MSDSs and SOPs for sampling precautions.
• Follow the sampling instructions exactly, which should specify sample size, sample number, and location of sampling.
• Only operators trained in sampling technique should take samples.
• Reseal containers after sampling, and label the containers that have been sampled from.
• Ensure that the sample itself is properly labelled on the body of the container, not on the lid.

How Much Testing Is Required? The amount of testing will depend upon:

• The nature of the material
• The history of the supplier
• Whether there is a valid certificate of analysis
• The company’s QA program

Monitoring Stored Materials  Starting materials should be retested or re-examined after long storage or after exposure to adverse conditions. Stored starting materials may not be used for extended periods. If stored correctly, under controlled temperature conditions they will be good through to expiry date. Sometimes, the laboratory will want to retest materials before continuing use. This is usually a precaution for materials that could, for example, pick up moisture on storage. Status labelling Before it can be used, material must be releases for use by Control (QC), Once material has passed inspection and testing. QC will change the status from “Hold” / “Quarantine” to “Released” / “Approved”. The material can then be used in the manufacturing. Status labels may be either:

• Physical labels on the container
• Electronic fields on a database
• A combination of physical and electronic

Be familiar with the system your uses to ensure that only released materials are used. GMP Storage Requirements 

• Temperature must be monitored in storage areas, and the results must be regularly checked.
• There must be pest control program to ensure that raw materials are not contaminated by rats, mice, birds, cockroaches, etc.
• Any discrepancies in inventory must be investigated
• Items must be stored off the floor and away from walls
• Stores operate on a “First In, First Out” (FIFO) basis to ensure that the oldest material is used first.
• Only authorised personnel should be permitted into the storage areas. Visitors should be accompanied.
• GMP rules require separate areas for materials with different statuses, and the status of the material must match its associated location at all times.
• Regular stock takes are necessary to verify that the physical stock matches the paperwork.
• Starting materials and components must be stored in designated locations.

Protecting Raw Materials Because raw materials may deteriorate storage or become contaminated if stored incorrectly, the storage conditions are critical to product purity. In to protect raw materials are some specific and GMP rules relating to this:

• Separate quarantine and reject areas.
• The storage environment should be temperature-controlled.
• Store goods off the floor and away from walls.
• Employ a system that identifies material about to expire so that it can be retested if necessary.
• Periodically inspect stockrooms for past-expiry expired stock, cleanliness, housekeeping, and pest control.
• Seal over all opened containers to protect from the environment.

Issue of Materials The issue of approved materials must be performed only by designated staff. Other staff should never “help themselves”. If an incorrect material issued. a disaster such as a mix-up or product failure follow. Here are some important GMP rules regarding issue:

• Materials should only be issued from the store by authorised persons following a written procedure.
• Records of the quantities receipted into stock and the quantities issued to manufacturing must be maintained.
• Inventory records should be maintained in such a way that any discrepancy between the quantity received and the quantity issued can be clearly seen.
• Discrepancies are to be reported and investigated.

Computer Controlled Release GMP allows for a computer system to control status and allow release to manufacturing. If computer systems are in use, they must be validated and secure. Ensure that you know your computer system procedures and security controls. Only QA- Or QC-nominated personnel can change the status of material to “Released”, but every company has specific GMP rules in this area. GMP and Production There is a universal saving in the pharmaceutical industry: “You cannot test quality into products: quality must be built in at each step.” Having effective and validated process controls in place for all key steps of production ensures quality is built in. Testing can only defective product. Some basic GMP rules for production include:

• Always follow procedures. Report any deviations or abnormalities
• Process batches in accordance with master documents.
• Operators must be trained in SOPs.
• Online testing provides assurance that the product is within specification.
• Manufacturing records must be completed accurately and completely, and should include all information relating to processing and testing.
• Bulk containers and other major items of equipment should be labelled with the name, strength and batch number of product being processed.
• In-process items should be clearly labelled.
• Store materials in designated areas