Good Pharmaceutical Manufacturing Practice (GPMP)

GOOD PHARMACEUTICAL MANUFACTURING PRACTICE (GPMP)

GPMP is concerned with the manufacture of medicines, and includes control of ingredients, plant construction, process validation, production and cleaning. Current GPMP (cGPMP) requirements are found in the Medicines and Healthcare Products Regulatory Agency (MHRA) Rules and Guidance for Pharmaceutical Manufacturers and Distributors, known as the Orange Guide (Anon 2007), and its 20 annexes. QC is that part of GPMP dealing with specification, documentation and assessing conformance to specification. With traditional QC, a high reliance has been placed on testing samples of finished products to determine the overall quality of a batch. This practice can, however, result in considerable financial loss if non-compliance is detected only at this late stage, leaving the expensive options of discarding or reworking the batch. Additionally, some microbiological test methods have poor precision and/or accuracy. Validation can be complex or impossible, and interpretation of results can prove difficult. For example, although a sterility assurance level of less than one failure in 10⁶ items submitted to a terminal sterilization process is considered acceptable, conventional ‘tests for sterility’ for finished products (such as that in the European Pharmacopoeia) could not possibly be relied upon to find one damaged but viable microbe within the 10⁶ items, regardless of allowing for its cultivation with any precision . Moreover, end-product testing will not prevent and may not even detect the isolated rogue processing failure.

It is now generally accepted that a high assurance of overall product quality can only come from a detailed specification, control and monitoring of all the stages that contribute to the manufacturing process. More realistic decisions about conformance to specification can then be made using information from all relevant parameters (parametric release method), not just from the results of selective testing of finished products. Thus, a more realistic estimate of the microbial quality of a batch of tablets would be achieved from a knowledge of specific parameters (such as the microbial bioburden of the starting materials, temperature records from granule drying ovens, the moisture level of the dried granules, compaction data, validation records for the foil strip sealing machine and microbial levels in the finished tablets), than from the contaminant content of the finished tablets alone. Similarly, parametric release is now accepted as an operational alternative to routine sterility testing for batch release of some finished sterile products. Through parametric release the manufacturer can provide assurance that the product is of the stipulated quality, based on the evidence of successful validation of the manufacturing process and review of the documentation on process monitoring carried out during manufacturing. Authorization for parametric release is given, refused or withdrawn by pharmaceutical assessors, together with GMP inspectors; the requirements are detailed in Annex 17 of the 2007 Orange Guide.

It may be necessary to exclude certain undesirable contaminants from starting materials, such as pseudomonads from bulk aluminium hydroxide gel, or to include some form of pretreatment to reduce their bioburdens by irradiation, such as for ispaghula husk, herbal materials and spices. For biotechnology-derived drugs produced in human or animal tissue culture, considerable efforts are made to exclude cell lines contaminated with latent host viruses. Official guidelines to limit the risk of prion contamination in medicines require bovine-derived ingredients to be obtained from sources where bovine spongiform encephalopathy (BSE) is not endemic.

By considering the manufacturing plant and its environs from an ecological and physiological viewpoint of microorganisms, it is possible not only to identify areas where contaminants may accumulate and even thrive to create hazards for subsequent production batches, but also to manipulate design and operating conditions in order to discourage such colonization. The facility to clean and dry equipment thoroughly is a very useful deterrent to growth. Design considerations should include the elimination of obscure nooks and crannies (where biofilms may readily become established) and the ability to clean thoroughly in all areas. Some larger items of equipment now have cleaning-in-place (CIP) and sterilization-in-place (SIP) systems installed to improve decontamination capabilities.

It may be necessary to include intermediate steps within processing to reduce the bioburden and improve the efficiency of lethal sterilization cycles, or to prevent swamping of the preservative in a non-sterile medicine after manufacture. Some of the newer and fragile biotechnology-derived products may include chromatographic and/or ultrafiltration processing stages to ensure adequate reductions of viral contamination levels rather than conventional sterilization cycles.

In a validation exercise, it must be demonstrated that each stage of the system is capable of providing the degree of intended efficiency within the limits of variation for which it was designed. Microbial spoilage aspects of process validation might include examination of the cleaning system for its ability to remove deliberately introduced contamination. Chromatographic removal of viral contaminants would be validated by determining the log reduction achievable against a known titre of added viral particles.