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Product Quality Issues

In the past several years, it has been realized that many other issues in addition to bad reactions to the active chemical entity in the product play a significant role in drug safety and pharmacovigilance, because of the realization that a safety issue may be related to more than just the active ingredient (moiety). Excipients (see Chapter 5), residues from the manufacturing process, quality control (or lack thereof), the container and packaging, storage issues in the pharmacy or home, tampering, counterfeiting, and other adventures that occur before and after the product has left the factory can produce bad effects. So an adverse event (AE) is more than just a bad reaction to the active chemical entity. This chapter summarizes briefly issues that revolve around quality and manufacturing.

Patient or healthcare professional product complaints can revolve around the following:

• The drug did not work (lack of efficacy).
  
• The drug produced an AE (safety issue).
  
• The drug looked, tasted, or smelled funny or different. It was crumbling. There was a powder on the pill and so forth (product manufacturing or quality issue).
  
• The drug was a tablet in the past, but this time it was capsules (quality issue in packaging, dispensing, etc.).
  
• I want my money back or I am suing.
  
• I ordered these pills on the internet from a pharmacy supposedly in Canada (possible counterfeit or quality issue).
  
• I saw on the internet that this pill should….
  
• Others (“My dog accidentally ate the pills.”).

Frequently, one sees multiple issues with a single phone call: “The pill was the wrong color, and when I took it, I developed chest pain, and I want my money back or I’ll sue.” Part of the issue here involves getting the correct people within the pharmaceutical company (or health authority or call center if they are the first to receive the call) to act on each of the issues involved: the AE component, the product quality component, and the monetary/legal component. In this chapter, we address product quality issues.

Manufacturing is regulated in most countries and regions by a set of regulations, directives, laws, and guidances that go under the general rubric of “Good Manufacturing Practices,” or GMP. The International Conference on Harmonization (ICH) has addressed manufacturing issues in a series of “Quality Guidelines” (Web Resource 33-1), covering such topics as stability, analytical validation, impurities, and so forth. The key document is Q7: Good Manufacturing Practices. Each country or region has enacted its own requirements for GMP.

• In the United States in the Code of Federal Regulations section 21CFR211, Current Good Manufacturing Practice for Finished Pharmaceuticals
  
• In the European Union in Directive 2003/94/EC (Web Resource 33-2) for the United Kingdom in guidances and legislation (Web Resource 33-3)
  
• In Canada multiple guidances (Web Resource 33-4)

To a large degree, the GMP requirements are quite similar around the world, and one factory will frequently produce products sold in many (or all) global markets, thus meeting all standards.

In the United States, the specific section covering product quality issues is 211.198 Complaint Files:

This section obliges the manufacturer to maintain written procedures on the handling of all complaints and specifies that a review must be done for serious and unexpected AEs. The U.S. Food and Drug Administration (FDA) performs inspections (more than 22,000 in 2004 but dropping to 15,000 in 2008). The FDA has committed to increasing its inspections, and product quality issues are often cited. An example follows from a Warning Letter to a pharmaceutical company:

The responsibility for investigating product complaints generally falls within the competence of one of the quality units in a company. The drug safety department usually becomes involved when there is a product quality complaint, a medical error, or an AE. That is, even though there was an issue with the manufacturing or quality of the product, the subject took the product and had an AE. Sometimes, of course, the quality issue is only discovered or noted after the use of the product (e.g., the patient had an AE and went back to look at the package and noted the tablets smelled funny and were off-color—a quality issue).

Within the pharmaceutical company, this is a “double issue,” with an evaluation of the AE by the drug safety group and an evaluation of the product complaint by the quality unit and the manufacturing unit concerned. There are several critical operational issues:

• All units (e.g., drug safety, manufacturing, and quality control) must be informed that the other units are involved in the same case if the case was received and triaged elsewhere (e.g., in Medical Affairs or Medical Communications). Each unit follows its procedures and does its evaluation, usually simultaneously.
  
• The units must communicate their findings to each other because one or both will likely be required to submit the findings to the health authorities. A mechanism must be developed to request that the patient who filed the complaint return any unused product to the company for analysis. Some companies do this for all complaints, whereas others set up specific criteria for requests for return of product. The quality workup may include reviewing batch records, testing the retained sample, and testing the sample returned by the patient.
  
• The results of this testing must be conveyed to the drug safety unit to include in the report to the FDA and any other concerned health authorities. If this is an expedited report, the quality unit must get the new information to the drug safety unit so that the follow-up to the agencies is done within the required time (often 15 calendar days or less for serious issues). The quality unit must not delay sending the information to the drug safety group. Similarly, relevant clinical follow-up information (e.g., lot numbers) from the drug safety unit should be forwarded immediately to the quality unit on the case.
  
• The case may have two or more different identification numbers—one in the drug safety unit and the other in the quality unit. If the computer system(s) cannot handle the two numbers for the same case, then another method of tracking must be developed to ensure that the case does not fall through the cracks. For large companies, the volume of such investigations may be quite high, with many data flowing back and forth between the departments. In addition, a third or even fourth department may be involved if the case involves a refund of money to the patient or a possible legal or police action (e.g., a lawsuit or police investigation for tampering).
  
• Now that the manufacture of many products is outsourced and sometimes done in more than one factory (e.g., one for raw materials and another for finished product and packaging), coordination and investigation may become complex and require careful and meticulous coordination and tracking.
  
• AEs and product quality complaints are now considered “two sides of the same coin.” That is, if an AE occurs after taking a drug, it is not always evident that the event is due to the active ingredient. It might be due to an excipient or a problem in manufacturing, storage, or shipping, or perhaps the product is a counterfeit. It is good pharmacovigilance practice for the drug safety group or the pharmacovigilance or risk management group to examine product quality issues on a regular basis to determine whether a clue or suggestion indicates that quality issues have produced AEs. The methodology for this evaluation (the relationship of quality issues to AEs) has not been fully harmonized yet and remains a methodology of “global introspection.” Some of the newer safety databases are now able to capture product quality issues for cases in addition to the usual AE data. The analysis should attempt to see whether there are similar cases (AEs and product complaints) seen with that product’s lot, batch number, or geographic area. (Mail-order pharmacy systems distributing drugs from centralized locations to all parts of the United States now make geographic tracking much harder and less useful. The days when a particular batch of a drug was used in a localized geographic area are disappearing in the United States but less so in smaller countries or regions).
  
• Significant and severe product quality issues, in particular those that risk patient health or produce serious AEs or suggest tampering, must be acted on immediately. The pharmaceutical company must have a mechanism in place to recognize such issues, investigate them, and bring the information in a timely fashion to the responsible levels of the company and the health agencies. If necessary, a product may need to be withdrawn immediately, public and internet/social media announcements made, protocols stopped, and so forth. The company should have a procedure whereby the team that would need to perform these actions is easily mobilizable for action.
  
• Many of the AE/product quality issues are often small and noncritical. Examples include the discovery that a part of the packaging (e.g., vials or stoppers) was obtained from a new vendor and looked or acted differently, or late stability testing showed problems. Sometimes it is discovered that a part or procedure was slightly but clearly out of specification. The determination of how far to proceed in terms of analysis and recall of products is often a difficult decision that requires the assistance of multiple departments within the company and the concerned health agencies. Complications can arise if one health agency wants or demands a recall and another does not. A formal written procedure must be developed and used.

The definitions of recalls and withdrawals in the United States are as follows:

• Class I recall: a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death.
  
• Class II recall: a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.
  
• Class III recall: a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.
  
• Market withdrawal: occurs when a product has a minor violation that would not be subject to FDA legal action. The firm removes the product from the market or corrects the violation. For example, a product removed from the market due to tampering, without evidence of manufacturing or distribution problems, would be a market withdrawal.
  
• Medical device safety alert: issued in situations in which a medical device may present an unreasonable risk of substantial harm. In some cases, these situations are considered recalls.

Examples of recalls, withdrawals, and safety alerts can be seen at the FDA’s website (Web Resource 33-6), including a partial listing of some of the recalls in early 2010 for drugs (Web Resource 33-6) and biologics (Web Resource 33-7) in the following two sections.

Drugs

• Alli 60 mg capsules (120-count refill kit): Counterfeit product
  
• Atlas Operations, Inc.: Recall of sexual enhancement products
  
• Avandia (rosiglitazone): Ongoing review of cardiovascular safety
  
• Benadryl Extra Strength Itch Stopping Gel: Packaging changes to reduce use errors
  
• Camolyn eye drops, Fisiolin nasal drops: Voluntary recall due to nonsterility
  
• Erythropoiesis-Stimulating Agents (ESAs): Procrit, Epogen, and Aranesp: Drug safety communication
  
• Exjade (deferasirox): Boxed warning
  
• GnRH Agonists: Safety review of drug class used to treat prostate cancer
  
• Heparin: Change in reference standard
  
• Invirase (saquinavir): Ongoing safety review of clinical trial data
  
• Long-Acting Beta-Agonists (LABAs): New safe use requirements
  
• Maalox Total Relief and Maalox Liquid Products: Medication use errors
  
• MasXtreme Capsules (Natural Wellness): Product contains undeclared drug ingredient
  
• McNeil Consumer Healthcare Over-the-Counter Infants’ and Children’s Products: Recall
  
• McNeil Consumer Healthcare Over-the-Counter Products: Recall
  
• Meridia (sibutramine hydrochloride): Follow-up to an early communication about an ongoing safety review
  
• Metronidazole injection 500 mg/100 mL: Voluntary recall due to nonsterility
  
• MuscleMaster.com Products Sold on Internet as Dietary Supplements: Recall
  
• Oral Bisphosphonates: Ongoing safety review of atypical subtrochanteric femur fractures

Biologics

• Important Notice RabAvert Rabies Vaccine (Rabies Vaccine for Human Use) Kits
  
• Important Information Regarding Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal Expiration Dating
  
• Recall of AMICUS Ancillary PL2410 Plastic Storage Container 4R2350
  
• Recall of Prevnar Pneumococcal 7-valent Conjugate Vaccine, Wyeth
  
• Market Withdrawal of Chiron RIBA HCV 3.0 SIA
  
• Recall of Influenza A (H1N1) 2009 Monovalent Vaccine
  
• Field Correction of Influenza A (H1N1) 2009 Monovalent Vaccine in Prefilled Syringes
  
• Recall of Y-Type Blood Solution Sets
  
• Field Correction of Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal Expiration Dating

Generally, most countries have mechanisms for emergency recalls or withdrawals from the market of products that have severe or dangerous or high-risk quality problems. This may be for the entire drug or only for certain formulations, lots, or other subgroups. These may be handled as expedited, reports or “rapid alerts” in the European Union. Although the safety group may be closely involved, the operational issues of the withdrawal or alert will involve multiple groups, including manufacturing, regulatory, legal, and communications (if the public has to be contacted).

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