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.

The discussion in India following the resolution of my case against Ranbaxy has been primarily focused on violations of processes that the U.S. Food and Drug Administration (U.S. FDA) requires pharmaceutical companies to follow.  The general theme of the discussion is that, while the U.S. FDA requires compliance with detailed processes for manufacturing drugs and establishing drug stability, Indian regulators do not have such strict requirements.  Others have stated that violations of detailed processes do not necessarily result in poor quality drugs.

In response to this discussion, the Indian Health Ministry offered an assurance to the public that it considers products manufactured by Ranbaxy – and other generic manufacturers – to be of high quality.  This response from the Ministry of Health (and others in the medical field) is understandable. Any statement to the contrary would have created a panic in the delivery of healthcare in India.  Indeed, one incident with Ranbaxy should not be used to paint the entire Indian generic industry with a broad brush.

Having said that, there are two important aspects of this discussion that need closer attention.

1. How do we establish quality when the processes by which drugs are manufactured are not sufficiently described and documented?
2. What kind of data do regulators need in order guarantee drug quality to the public?

Comparing Indian and U.S. Standards

The U. S. FDA has a Quality Systems Model that represents a framework for compliance with the Current Good Manufacturing Practices (cGMPs) (21 CFR Parts 210 and 211). Its prime directive is: “Quality should be built into the product; testing alone cannot be relied [upon] to ensure product quality.” This is the U. S. FDA’s stated approach to compliance and is available online.

In India, however, there is no such policy to define what constitutes “standard quality.” Drug The Controller General of India (DCGI) tests commercial samples following complaints, known as an adverse events, from consumers.  The Central Drugs Standard Control Organization (CDSCO) publishes a list of products that are tested by the central laboratories, which are found to be “not of standard quality.”

It also is instructive to compare how regulations are framed in both countries to understand minimum expectations of high-quality products.  In India, cGMP standards are described in Schedule M; in the U.S., the Code of Federal Regulations, Title 21, Volume 4 governs these standards.  For example, in the area of training and skill of personnel employed in the manufacturing facilities, India’s Section 6 of Schedule M describes the role of the management, operators, staffing and training in general terms. There are more stringent and defined requirements in the U.S.  Subpart B of Part 211 of the CFR, which governs organizational and personnel standards, states that:

There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

Such detailed expectations are missing in the Indian regulations.  Although there are additional clauses elsewhere in Schedule M that govern the rejection of products that fail tests, there is nothing as explicit as what is the law in the U.S. on how the process ought to work. There are many such examples in Indian regulations.

Why Processes and Standards Matter

Why is this important? Inspectors generally check compliance with stated regulations to establish variance from standard processes. If there is no explicit expectation of independence of the personnel and management in the quality-control unit, why should anyone be surprised if records, documents, and final products released to the public haven’t gone through rigorous checks for quality?

Violations of such processes result in significant penalties in the U.S.  Historically, the same cannot be said about India.

Rigorous compliance with detailed and established processes and systems is a key determinant of the quality of the product. Business process excellence requires definition of the process in detailed steps, its dependencies and associated decision criteria so that the process can be executed consistently by a trained operator.

By way of comparison, the Indian information technology (IT) industry has used this approach as a key differentiator in its growth.  SEI CMM is a standard that most Indian IT companies adhere to. ISO 9001 and other certifications require clear definition and adherence to detailed process. The reason these frameworks and certifications require adherence to a well-defined, detailed process is because consistency and repeatability across each step of the process leads to a better quality of the overall product. I believe this adherence to detailed process is why the IT industry from India is proving so globally competitive.

Improving Adverse Event Reporting

In safeguarding drug safety, compliance with processes and standards is particularly important when it comes to adverse event reporting—which is how regulators learn of problems with drugs already in the market. The U.S. has a well-established system to collect and analyze adverse event data. It is easily accessible to the consumer, and regulations require compliance with reporting both individual cases and annual aggregate reports that provide an analysis of trends for a particular drug product. The systems and processes needed to collect such data are still nascent in India.

Historically, reporting of adverse events for generic products lags behind that for branded products in the U.S. This needs to change.  The U. S. FDA continues to educate consumers of the need to report adverse events. However, the frequency of reporting adverse events for the same products (generic formulations) in India is significantly lower compared to the U.S.  Although the Indian regulator requires submission of periodic aggregate safety data, it is not clear what actions result from the analyses of such data. Regulatory actions seem to be driven more by international incidents (recalls, judgments etc.) than the results of analysis of aggregate safety data.

It’s worth noting that safety is a good surrogate for product quality, a case that I have made before on this blog. There are many such sources of data that are key to a sound scientific decision-making process used by the U. S. FDA. Unless the regulatory framework makes it a priority to collect and analyze such safety and adverse event data, assertions to the superior quality of products dispensed in the Indian market will remain subjective.

FDA Has Approved Only a Fraction of India’s Drug Manufacturers

According to the DCGI, there are 169 manufacturing facilities in India approved by the U.S. FDA, 160 facilities approved by European regulators, and approximately 1,300 certified by the World Health Organization.  Overall, the DCGI estimates there to be about 8,000 manufacturing units across the country. Industry estimates put that number as high as 20,000.

The facilities that are inspected by the U.S. FDA and European Regulators have to comply with detailed processes and standards that govern the manufacture of medical products sold in those countries. Can we say the same about the other manufacturing facilities that cater primarily to the local market? Do we really have the confidence that the drugs manufactured in these facilities are in-fact of high quality?