Between 1995 and 1996, Haiti saw incidents of around 80 children dying after ingesting a cold-and-cough syrup. An investigation fixed the responsibility on glycerol in the product being contaminated with diethylene glycol. Raw Material and other such incidents highlight the need for drug product manufacturers to pay attention to the quality of starting materials they use.
While active pharmaceutical ingredients (APIs) may be manufactured under cGMP (current Good Manufacturing Practices), excipients may not be so produced, especially the ones commonly used in other industries like cosmetics or food. This makes it even more important to ensure these excipients are of a grade suitable for pharmaceutical use. Containers and closures must also be evaluated because they play a vital role in ensuring the product stays stable and safe throughout the shelf life.
Purchase of Materials
Purchasing must be done by staff with a thorough knowledge of those materials and their suppliers. Materials must be procured only from approved suppliers who have consented to provide materials in keeping with the quality specifications of the drug product manufacturer. It is advisable for pharmaceutical manufacturers to enter into contracts with specific vendors after performing a vendor audit that provides an assurance of raw material and packaging materials of the desired level of safety and meeting quality standards.
Receiving, handling, and storage of materials
Specific written procedures must be prepared to describe how raw material (both drug components and drug containers and closures) will be received, identified, stored, handled, sampled, tested, and accordingly approved or rejected, and these procedures must be followed as written.
When receiving materials, the consignment must be visually examined and the labels checked to confirm the content, quantity, integrity of seals and to verify that there is no damage or contamination. Any damaged containers found must be separated, and details recorded and informed to the supplier.
The materials must be stored under quarantine until samples have been drawn and tests have been performed. They must not be issued for use before approval.
Handling and storage of all materials in the storage area must be done in such a way that there is no contamination. Boxes or bags holding containers and closures must be stored off the floor. The storage must be done in a way that suitable space is left for proper cleaning and inspection of the materials.
Representative samples must be drawn from each shipment of each lot. If different batches are present in a single shipment, samples must be drawn from each of those. The quantity must be sufficient to perform all required tests and reserve when specified. Statistical criteria must also be used to determine the number of samples drawn. Containers must be cleaned before sampling to avoid introducing contamination and resealed after sampling to prevent contamination of the contents and appropriately labeled to show sample has been taken. Samples must be drawn from the bottom, middle, and top of the containers, and marked accordingly. Sample-holding containers shall be labeled with details of the name of the material, lot number, container number, date of sampling, and name of the person collecting the sample.
Testing of Samples
At least one specific test must be performed to verify the material’s identity. Tests must be carried out to determine conformity with predetermined specifications for quality, strength, and purity. In case materials are supplied along with a certificate of analysis by the supplier, the materials may be used without sampling and testing, provided the supplier is a reliable, validated vendor and at least one specific identity test has been performed and mentioned in the certificate.
Materials that are liable to contamination with adulterants, insect infestations, or filth must be examined for such contaminants. If materials are prone to microbial contamination, microbiological tests must be performed to test for them.
Approval/Rejection of Materials
All materials that meet the manufacturer’s quality requirements of identity, quality, purity, strength, and other tests are to be approved for use. Raw Material not meeting these requirements must be rejected.
Labels must carry the name of the product, the company’s unique reference code, manufacturer’s name and address, and their assigned batch number. It must also state the status of the contents (For example – “Sampled”, “Quarantined”, “Approved” and “Rejected”), manufacturing and expiry dates, and re-test date. When attaching such labels, care must be taken that original information on the supplier’s label is not lost.
Approved materials must be so marked while rejected materials must be conspicuously labeled and stored in a separate area to avoid chances of mix-ups or misuse.
Using Approved Materials
Approved materials must be stored properly and issued for use in a way such that the earliest approved stock is used first before more recently approved stock. Many companies use a FEFO (First Expire First Out) system for stock rotation. Another deciding factor is that the drug product’s shelf life must not exceed the shelf life of the APIs.
If materials have been stored for a very long period without usage, or if they have been exposed to any condition that may have an adverse effect on their quality or safety, they must be re-tested for the same parameters as the initial test. Results of the re-test must be used to determine if the materials are approved or rejected.
Handling Rejected Materials
Rejected materials must be identified with appropriate labels and kept in quarantine until safely disposed of. Care must be taken to prevent the use of such materials in manufacturing operations.
Containers and Closures
Containers and closures are used for the packing of drug products must not be additive, reactive, or absorptive. This is important to ensure they do not cause a change in the identity, safety, quality, strength, or purity of the drugs beyond specifications.
Closures and containers must be capable of protecting the drug product from external conditions that may cause its contamination or deterioration.
Containers and closures must be clean and if required, sterilized to remove contamination by microorganisms and pyrogens.
Note: If computerized storage systems are used, they must be fully validated to prove they work reliably.
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