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Labelling and packing
After the product has been filled (and sealed) in its final product container, it is immediately placed under quarantine. QC personnel then remove representative samples of the product and carry out tests to ensure conformance to final product specification. The most important specifications will relate to product potency, sterility and final volume fill, as well as the absence of endotoxin or other potentially toxic substances. Detection and quantification of excipients added will also be undertaken.
Only after QC personnel are satisfied that the product meets these specifications will it be labelled and packed. These operations are highly automated. Labelling, in particular, deserves special attention. Mislabelling of product remains one of the most common reasons for product recall. This can occur relatively easily, particularly if the facility manufactures several different products, or even a single product at several different strengths. Information presented on a label should normally include:
• name and strength/potency of the product;
• specific batch number of the product;
• date of manufacture and expiry date;
• storage conditions required.
Additional information often presented includes the name of the manufacturer, a list of excipients included and a brief summary of the correct mode of product usage.
When a batch of product is labelled and packed, and QC personnel are satisfied that labelling and packing are completed to specification, the QC manager will write and sign a Certificate of Analysis. This details the pre-defined product specifications and confirms conformance of the
THE DRUG MANUFACTURING PROCESS 159
actual batch of product in question to these specifications. At this point, the product, along with its Certificate of Analysis, may be shipped to the customer.
ANALYSIS OF THE FINAL PRODUCT
All pharmaceutical finished products undergo rigorous QC testing, in order to confirm their conformance to pre-determined specifications. Potency testing is of obvious importance, ensuring that the drug will be efficacious when administered to the patient. A prominent aspect of safety testing entails analysis of product for the presence of various potential contaminants.
The range and complexity of analytical testing undertaken for recombinant biopharmaceuticals far outweighs those undertaken with regard to ‘traditional’ pharmaceuticals manufactured by organic synthesis. Not only are proteins (or additional likely biopharmaceuticals, such as nucleic acids; Chapter 11) much larger and more structurally complex than traditional low molecular mass drugs, their production in biological systems renders the range of potential contaminants far broader (Table 3.25). Recent advances in analytical techniques renders practical the routine analysis of complex biopharmaceutical products. An overview of the range of finished-product tests of recombinant protein biopharmaceuticals is outlined below. Explanation of the theoretical basis underpinning these analytical methodologies is not undertaken, as this would considerably broaden the scope of the text. Appropriate references are provided in Further Reading at the end of the chapter for the interested reader.
Most of the chromatographic steps undertaken during downstream processing are specifically included to separate the protein of interest from additional contaminant proteins. This task is not an insubstantial one, particularly if the recombinant protein is expressed intracellularly.
In addition to protein impurities emanating directly from the source material, other proteins may be introduced during upstream or downstream processing. For example, animal cell culture media is typically supplemented with bovine serum/fetal calf serum (2-25%), or with a defined cocktail of various regulatory proteins required to maintain and stimulate growth of these cells. Downstream processing of intracellular microbial proteins often requires the addition of endonucleases to the cell homogenate to degrade the large quantity of DNA liberated upon
Table 3.25. The range and medical significance of potential impurities present in biopharmaceutical products destined for parenteral administration. Reproduced by permission of John Wiley & Sons Ltd from Walsh & Headon (1994)
Impurity Medical consequence
Microorganisms Potential establishment of a severe microbial infection --- septicaemia
Viral particles Potential establishment of a severe viral infection
Pyrogenic substances Fever response which, in serious cases, culminates in death
DNA Significance is unclear ---could bring about an immunological response
Contaminating proteins Immunological reactions. Potential adverse effects if the contaminant exhibits