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• exact packing instructions (e.g. how many units of product per pack, how may packs per shipping carton, etc.).
A copy of the label to be used is generally attached to the documents, to allow the supervisor and operators to verify easily that the correct label has been dispensed for the product in question.
Maintenance of adequate and accurate records forms an essential part of GMP. For any given batch of product, records relating to every aspect of manufacture of that batch will be retained. These records will include:
• specification results obtained on all raw materials;
• batch manufacturing, processing and packaging records;
• QC analysis results of bulk and finished product.
These records, along with samples of finished product, must be retained in the facility for at least 1 year after the expiry of that batch. Should any difficulty arise regarding the finished product, the records should allow tracing back of all direct manufacturing steps, as well as indirect procedures which might influence the quality/safety of the product. During inspections, regulatory inspectors usually examine the records relating to a number of randomly chosen batches in detail, in order to help them assess ongoing adherence to GMP in the facility.
Generation of manufacturing records
Prior to commencement of the manufacturing of a specific product, production personnel will print/photocopy the manufacturing formulae, processing and packaging instructions associated with that product. The responsible individual fills in the batch number in the space provided (a batch number is a unique combination of numbers and/or letters assigned to that batch, in order to distinguish it from all other batches). This photocopied document forms the blueprint for manufacture of that batch. A space is provided after each manufacturing/packing instruction. When that step is completed, the responsible operator initials the space and includes the exact time and date undertaken. This forms a detailed record of manufacture.
Additional supporting documents are also included in the manufacturing records. These may include computerized print-outs from weighing equipment used to dispense chemical raw materials, or recorder charts obtained, e.g. from a freeze-drier upon completion of freeze-drying that batch of product.
QC records relating to raw materials, in-process and final product are generated in much the same way — by printing/photocopying originals and filling in the test results obtained.
Advances in information technology are now impacting upon the pharmaceutical industry. Many documents are now maintained in electronic format. In fact, some regard it as likely that in the future ‘paperless facilities’ will become commonplace, with all documentation being computerized. Several aspects of such electronic document maintenance deserve special attention. Adequate back-up files should always be retained. Also, restricted access to computerized systems is required to ensure that data/documentation is only entered/amended by persons authorized to do so.
SOURCES OF BIOPHARMACEUTICALS
The bulk of biopharmaceuticals currently on the market are produced by genetic engineering using various recombinant expression systems. While a wide range of potential protein production systems are available (Table 3.8), most of the recombinant proteins that have gained marketing approval to date are produced either in recombinant Eschericia coli or in recombinant mammalian cell lines (Table 3.9). Such recombinant systems are invariably constructed by the introduction of a gene or cDNA coding for the protein of interest into a well-characterized strain of the chosen producer cell. Examples include E. coli K12 and Chinese hamster ovary strain K1 (CHO-K1). Gene/cDNA transfer is normally achieved by using an appropriate expression plasmid, or other standard gene-manipulating techniques. Each recombinant production system displays its own unique set of advantages and disadvantages, as described below.
E. coli as a source of recombinant, therapeutic proteins
Many microorganisms represent attractive potential production systems for therapeutic proteins. They can usually be cultured in large quantities, inexpensively and in a short time, by standard methods of fermentation. Production facilities can be constructed in any world region, and the scale of production can be varied as required.
The expression of recombinant proteins in cells in which they do not naturally occur is termed ‘heterologous protein production’. By far the most common microbial species used to produce
Table 3.8. Expression systems that are/could potentially be used for the production of recombinant biopharmaceutical products (CHO = Chinese hamster ovary; BHK = baby hamster kidney)
E. coli (and additional prokaryotic systems, e.g. Bacilli) Yeast (particularly Saccharomyces cerevisiae)
Fungi (particularly Aspergillus)