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International GMPs

Future Trends – GMPs and Risk Assessment

The first versions of the Canadian GMPs, published in the early 1970s was  unique in that it scored a company on its degree of GMP compliance. Not only was it a requirement for the company to comply with the GMPs in totality, it had to also attain a passing grade within each section of the GMPs (production, packaging, sanitation, laboratories, etc.). While this approach was never formally adopted by other countries, it appears to have been the first attempt by any national authority to establish a risk based approach to GMP compliance.

In the US, GMP compliance is regarded as being total. In reality any GMP inspection can only review 5 – 10% of a company’s activities, and a company needs to be 100% ready for what is effectively a 5% inspection. Many in the US pharmaceutical industry have come to regard this attitude as a waste of valuable resources, and would rather see a risk based approach to GMP compliance. Patients are more likely to die when an injectable product is manufactured not in accord with GMPs, than when a cream is so manufactured. Thus it would seem to some that GMP resources should be directed to those elements of operations that most put patients at risk – for example should as much effort be expended in inspecting whether all training is fully documented or whether product labels are  mixed up.

This attitude has given rise to the use of quality assurance tools widely used in other industries to attempt to design systems that do not fail, or to design systems where failure is always detected. The use of Failure Mode and Effects Analysis (FMEA) widely used in the electronics and medical device industries, and Hazard Analysis and Critical Control Points (HACCP) techniques taken from the food industry are beginning to be thought of by the pharmaceutical industry as tools to augment GMPs and eliminate activities considered to be wasteful practices mandated by GMPs. Examples of these ‘wasteful’ activities are: the needs for line clearance, the need for two persons to perform weighing, the need for in-process testing when the process has been validated, and even a questioning of the need for finished product laboratory testing, mandated by GMP regulations, when current technology allows for 100% in-line identification and potency testing of every single tablet coming off a tablet press.

FDA has indicated a willingness to consider revising its GMP regulations when faced with evidence that current technology can in fact ensure or improve the standard of quality as defined by the current GMP regulations.

The Australian authorities have for several years embarked on a risk analysis approach to their inspections by grading their inspectional findings as critical, major or minor, an approach that with the exception of Canada is not currently employed by any other agency inspection. In the Australian scheme, deficiencies are defined in the following ways:

  • A Critical Deficiency is a deficiency which indicates a significant risk that product could or would present a risk to the patient
  • A Major Deficiency is a non-critical deficiency which could or would produce a product which is not in accordance with the product filing; or which indicates a significant deviation from GMP
  • A Minor Deficiency a deficiency which is neither critical or major, but which indicates a departure from the product filing or GMP

Such organization of GMP deficiencies, by scale of concern to the patient, goes a long way in bringing industry and regulators onto the same wavelength as to what is important in the manufacture and testing of pharmaceutical products.

The Canadian HPFBI has taken this concept even further by classifying both drug products and the GMP non-compliance observations found under their “Risk Classification of GMP Observations” scheme.  The Canadian scheme takes the Australian definitions a step further. In Canada:

  • A Critical observation is an observation describing a situation that is likely to result in a non-compliant product or a situation that may result in an immediate or latent health risk and any observation that involves fraud, misrepresentation or falsification of products or data.
  • A Major observation is an Observation that may result in the production of a drug not consistently meeting its marketing authorization.
  • An Other (or minor) observation is an Observation that is neither critical nor major but is a departure from the GMP

Additionally the Canadians also apply a categorization to drug products as to whether the product is critical or not. A Critical product is one that falls into any of the following criteria:

  • The product has a narrow therapeutic window
  • The product has a high toxicity
  • The product is a sterile product or a biological drug, or
  • The product requires a complex manufacturing process – this being a process for which slight deviations in the control of parameters could result in a non-uniform product or a product not meeting its specifications. (As an example, powder mixing or granulation for low dosage solid forms, long acting / delayed action products, sterile products).

Hence a critical observation occurring in a critical product gives rise to immediate regulatory action of the severest kind.

A description of the Canadian system of classification of GMP risk can be found at the HPFBI website at



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