Product Quality Issues and Drug Safety

Oct 09, 2013
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Product quality issues, particularly for marketed drugs, is an area that many in drug safety do not pay too much attention to.  This is unfortunate in many regards: FDA and other regulators expect companies to be aware of and act immediately on any product quality issues and this includes safety reporting if there is an adverse event (AE) involved.

Product Quality Issues

As is expected, even in the best and most careful of companies, sometimes products are released to the market that have problems.  This is expected in any human endeavor, particularly those involving complex manufacturing processes.  In the US pharma industry, manufacturing must normally be done under Good Manufacturing Practices (GMP).  Similar requirements exist in many countries and regions including the EU.  The WHO has also put out GMP. In the US these date back to the 1938 Food, Drug and Cosmetic Act.

The expectation and requirements of these laws, regulations and directives is that manufacturing will be done using clearly defined, controlled and consistent practices.  The end product must meet predetermined specifications concerning content, quality, appearance, etc.  There must be written procedures that are followed with detailed and meticulous record keeping which will allow a root cause analysis (“failure analysis”) to be done in case of problems.

Yet, stuff happens.  To get an idea of the magnitude of this situation, have a look at the FDA’s frequently updated recall postings  of food, drugs, animal health product,s biologics, devices and cosmetics at  In the first four days of October, there were 6 recalls including: lidocaine injection (steel particulate matter in the product), ciricothyrotomy kits (defective balloon), turmeric spice powder (excess lead), plums (undeclared sulfites), metoclopramide and ondansetron (glass particulate matter).

When a recall or market withdrawal occurs, there are certain obligatory steps that must be taken.  This is a complex area and if you wish to pursue you can look at, amongst other articles and FDA’s website, a publication I wrote on this: in February 2011 in the Regulatory Affairs Journal entitled: Taking A Proactive Approach to Product Recalls and Withdrawals

Most of these recalls and withdrawals do not cause significant problems.  But every now and then adverse events of varying severity can occur causing the recall.   This touches drug safety and I will address this in a posting in the near future.

The direct requirement in the US for a drug safety regarding product quality complaints is found in 21CFR211.198 which states:

“Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for re- view by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with Sec. 211.192. Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration.”

The part that concerns drug safety is in the last sentence where the law states that there must be a system to determine whether an unexpected SAE has occurred and, if so, whether it must be reported to FDA.

This is obviously taken seriously by FDA and has been cited in various communications to companies after inspections and even in some Warning Letters to companies.  Usually the issues cited revolve around the company either not having adequate written procedures in place to evaluate such product complaints or failing to follow them.

So what should be in place? So, what actually is a product quality complaint?

“Product complaints” or “product quality complaints” are broadly described to include a multitude of issues including manufacturing problems, storage issues, contamination, out of specification products, medical errors and adverse events.

First there must be clear responsibility in the company within the appropriate departments to identify, track and actively follow up on complaints.  For most of the ones listed above, this falls in the domain of one or more of the Manufacturing, Compliance or Quality groups.  Adverse events will fall, of course, ultimately into the drug safety group.  Medical errors can be a bit more nebulous and may or may not end up in the drug safety group.  The Medical Information and call centers must also be aware of the requirements to act on complaints and ensure that they are captured and expeditiously sent to the appropriate places.

There are several things a company must have in place:

Firstly, there must be written SOP or other procedural document defining product quality complaints, who is responsible and what they must do.  Usually the personnel involved would be the head of drug safety (DS)/pharmacovigilance (PV), the head of Manufacturing, the head of Quality Assurance and the head of Compliance.  These individuals may, of course, delegate specific operational functions to others but a senior level executive should be the responsible person within each group.  If the SOP covers both clinical trials and post-marketing situations then medical personnel from these groups should also be included in the SOP.

The first step in the SOP is to ensure that the product quality complaints are picked up, appropriately identified, triaged and sent to the right departments rapidly, if not immediately – usually within 1 working (or better, business) day.  Thus the manufacturing quality issue and the adverse event (if any) must be immediately triaged.  Other possible issues with this lot or batch should be identified in drug safety and in manufacturing or wherever such cases are stored.  That is, it should be determined whether the complaint is an isolated one or is part of a bigger problem.  If the latter, a case series should be developed.  The review should be worldwide if the product is marketed or studies outside one country.  Attention should be paid to possible geographic clustering.

The manufacturing/quality personnel will need to determine whether the problem requires a rapid report to the regulatory authorities (e.g. an FDA 3 day field alert) and will need to do a root cause analysis to look for issues in manufacturing, storage, shipping, packaging etc.  In particular, process changes or the use of new vendors or suppliers in manufacture should be sought.

If there is an AE, or worse an SAE, DS/PV must also begin its investigation and handle the SAE/AE as it normally would but with the additional requirement that they work closely with the manufacturing/quality people handling that part of the work-up.  Information must be exchanged in real-time or near real-time as DS/PV must include any relevant manufacturing or quality information in its IND or NDA expedited reports and the manufacturing people must include safety information in their reports to FDA, in particular, in the medical analysis that must be included in many urgent regulatory reports around the world.  I’ll talk about this in a future posting.

If DS/PV does not have an SOP covering these “combo cases” then one should be developed and implemented or the need requirements should be put into an existing SOP on SAE/AE case handling.

As always, follow-up must be done to ensure that case information is as complete as possible.

If the case or cases turn out to be possible signals, then this issue should be passed on to the Signal Committee in the company for evaluation.  If the complaint turns out to be an emergency in terms of immediate recall or risk to the public health, the company must invoke its “Crisis SOP” which usually involves calling an immediate meeting of the head of Regulatory, Legal, Medical, Drug Safety, Compliance and perhaps others.  Again, think global not just the US or the company’s mother country.  Remember that there may also be business partners, co-marketers, co-developers etc.  If this is clinical trial material, there will be other possible additional steps such as notifying investigators, IRBs, patients, Data Monitoring Committees etc.

So the bottom line here is that every company selling or studying pharmaceuticals must have in place several policies and procedures to handle what may start out as an innocent-sounding phone call (“the pill was red instead of blue and when I took it my stomach hurt”). As always in drug safety, the next phone call, email or fax can be a major public health issue and, if not handled appropriately, a disaster.