Compliance today is continuous process of assessing and eliminating or minimizing risks associated with the manufacture of pharmaceutical product. The key objective of Current Good Manufacturing Practices (cGMPs) is to provide patients with a product that has an equivalent identity, safety, strength, quality and purity to the one which was used to establish the clinical efficacy during product development (bio-equivalence in the case of generic drugs).
Risk-based assessment of compliance with cGMPs focus on control of critical points in the manufacturing process that are needed to ensure that the finished product meets the quality attributes required for the patient use. Here is a rundown of key objectives of cGMPs and how they accomplish them:
- To asssure the patient that the product prescribed has equivalence to the one tested and for which market authorization was obtained. This means that the product weight, volume, dosage strength, potency and stability are identical to that which was used during clinical development.
- The active drug in the product must be bioavailable to the patient in a manner that was shown and tested in clinical studies. This leads to the requirements for dissolution and contributes to the requirements for stability. These two criteria form the basis of what the regulators call “adulterated” drugs.
- Foreign substances, cross-contaminants and any other extraneous materials that may impact the patient in an adverse manner must be prevented from being a part of the product through effective quality-control procedures. This leads to requirements for adequate maintenance and calibration of equipment in the manufacturing plant.
- The process by which the drug product is manufactured must be monitored and controlled so that there is consistency and repeatability of above characteristics to meet set standards of control. This leads to establishment of key outcomes, called “specifications” which qualify the process and the output product that can be tested to make sure the process is working as intended.
- The raw material that is used to prepare the final drug product is also a key area of control. Lately, sources of Active Pharmaceutical Ingredient (API), excipients and other chemical/biological substances used in the manufacturing process are located all the way across the globe. Majority of bulk API now comes from China and a lion’s share of formulation into the final drug product is done in India. Ensuring high standards of quality of input into the manufacturing process as it relates to the raw material is a key risk to overall product quality.
- Finally, the documentation associated with the entire manufacturing process must be adequately detailed to demonstrate that the process is sufficiently controlled. Good documentation is key to training new operators, providing guidelines for handling unanticipated situations and for assuring quality inspectors that the process consistently produces a quality product. It also helps identify any trends and provide traceability in conducting investigations when things go wrong.
While the above six areas of control may be commonsense, it is surprising to see how often they are not properly implemented. External inspections often focus on identifying discrepancies in the implementation of these processes; and as I have said in an earlier blog post, the geographical location of overseas manufacturing facilities present a more challenging scenario to ensure their implementation.
The recently released report on Countering Falsified and Substandard Drugs from the Institute of Medicine1 correctly articulates the following:
- Failure to adhere to good manufacturing practices is the root cause of substandard drugs.
- While any one test may suffice to label a drug substandard or falsified, no single analytical technique provides enough information to confirm that a drug is genuine.
- Neglect of good manufacturing practices, both accidental and deliberate, drives the circulation of substandard drugs, while falsification of medicines has its roots in crime and corruption.
- The cost of active ingredients is by far the largest fraction of overall cost. A small reduction in active ingredient can vastly increase the profit margin.
- Good quality comes at a price, either from equipment costs, better ingredients or the higher process cost of quality assurance.
It behooves us, therefore, to ensure that every manufacturer that supplies its product to our healthcare system is consistently following cGMPs. Beginning July 2013, the European Medicines Agency (EUMA) now requires a cGMP certification for all active pharmaceutical ingredients (APIs) imported into the EU. The certification should be issued by competent authority of the exporting country.
According to Directive 2001/83/EC, the Qualified Person (QP) of the finished product manufacturing authorization holder needs to sign a declaration stating that the active substance is manufactured in compliance with the detailed guidelines on good manufacturing practice for starting materials. This is a good first step. The challenge, as I have learned from my experience in the Ranbaxy case, will be to have an effective inspection program to verify the authenticity of the cGMP certification. As we now know, this is easier said than done.
With the renewed focus on cGMP compliance and the significant gaps that I have seen in the implementation of the above controls in overseas manufacturing facilities, it is critical that pharmaceutical manufacturers pay special attention to this area and tighten up controls so that the patients who use their products are assured of the highest quality.