8.7.1 Impurities in Manufacturing Development
Impurities in pharmaceuticals are the other chemicals or products that are contained within the APIs. New impurities or higher levels of old impu- rities may surface during process development, scale-up, or storage. These could originate from the synthetic intermediates, during formulation or aging of both API itself or API in the drug product. Those of the key in- termediates may or may not convert to other impurities in the APIs. The appearance of impurities in any form or concentration may influence the efficacy and safety of the pharmaceutical products. Impurity profiling (i.e., the identity and quantity of impurity in the pharmaceuticals) is being given a superior consideration in this phase of drug development. Together with the ICH guidelines, the British Pharmacopoeia (BP) and the United States
Table 8.2 List of shortages on select categories by therapeutic class Therapeutic class
Number of critical shortages
Percent of critical shortages Anesthetic and central nervous
system drugs 37 17
Anti-infective drugs 34 16
Cardiovascular drugs 27 12
Nutritive drugs 18 8
Endocrine metabolic drugs 16 7
Gastrointestinal drugs 10 5
Oncology drugs 10 5
Diagnostic drugs 9 4
Blood modifier drugs 7 3
Musculoskeletal drugs 7 3
Ophthalmologic drugs 6 3
Respiratory drugs 6 3
Toxicology antidote drugs 6 3
Other* 18 8
Multiple therapeutic classes 8 4
Total 219 101**
From US Government Accountability Office (GAO), University of Utah Drug Information Service and Truven Health Analytics (Red Book). Report from June 2011 to June 2013 [19].
The Red Book is a compendium published by Truven Health Analytics that includes information about the characteristics of drug products.
*Includes other therapeutic classes, such as dermatological drugs and immunological drugs, as well as four drugs whose therapeutic classes were unavailable from the Red Book.
**Total does not sum to 100 due to rounding.
Pharmaceutical Formulation and Manufacturing Development: Strategies and Issues 181
Pharmacopoeia (USP) specify the guidelines for permissible impurity levels for the APIs or formulations. The impurities in an API that affect the quality and safety of drug products can be process or impact the quality and safety of drug products; they can be process related or environmentally induced (issues of stability). Acceptable impurity levels are very low as specified in the ICH regulatory documents. These could also be related or unrelated impurities. As stated in the ICH guidelines, any impurity at a level of ≥0.10% in the API should be identified and addressed accordingly. Typical examples are organic impurities (process and drug related), genotoxic impurities, polymorphic forms, inorganic impurities, residual solvents, and enantiomeric impurities.
Initial toxicology studies often determine the status of these impurities and if their levels in tested samples meet the acceptance criteria for qualifying these products [25,26]. Impurity status of drug formulation could change and this has become a daunting challenge in drug development.
8.7.2 Impurity in Drug Formulation
It is critical that the approved dosage form of the API be delivered to the patient, thus the solid state is expected to remain the same and unchanged throughout the drug lifecycle and in the monitoring processes. Approved dosage forms may exist as polymorphs, pseudopolymorphs, salts, cocrystals, and amorphous solids. Different mechanical, thermal, physical, and chemi- cal properties are unique to each of the solid forms. These variations in properties also alter the bioavailability, hygroscopicity, stability, and other performance characteristics of the drug. All this has been given serious con- sideration as these properties can have a deleterious impact on health if not properly controlled. Data from such studies inform the selection of the most suitable form for drug development. The critical properties of the API are:
appearance, solubility, impurities, stability, structure identity (crystalline or polymorphic), counter ions (salts) and crystals, chirality, d enantiomer(s), and other chemical and physical properties. These properties are contin- uously referenced throughout API scale-up process chemistry and GMP manufacturing.
8.7.2.1 Case II: Crystal Polymorphism in Pharmaceuticals
Ritonavir is the API of Abbott’s HIV drug Novir, marketed as an oral liquid and semisolid capsules for the treatment of AIDS, and was launched in 1996. It contains Ritonavir in ethanol/water-based solution, as the solid state did not exhibit the right physical–chemical characteristics to be effective as a drug. Therefore no crystal form control was required [27],
and only one crystal form was formulated, which was devoid of stability problems.
Later in 1998, the new polymorph had less solubility characteristics than the original crystal form. Final product lots failed the dissolution test, and a large portion of the drug substance precipitated out of the final (semisolid) formulated product. This resulted in the suspension of all manufacturing ac- tivities and the supply of this life-saving treatment for AIDS, followed by an urgent requirement to reformulate Norvir [28]. Abbott scientists revaluated and addressed the problem to better control the formation of either Form I or Form II polymorphs, which received FDA approval on reformulated Novir soft gelatin capsules in June 1999. The crystals would not have been found if not for the incidental supersaturation due to the cosolvent, the hydroalcoholic solution.
8.7.3 Genotoxic Impurities in Developing Drugs
Genotoxicity pertains to the ability of the drug to interact with DNA or DNA-associated biomolecules like enzymes and proteins. These can cause point mutations, and induce changes in chromosomal number or in chro- mosome structure in the form of breaks, deletions, rearrangements, muta- tions in germlines, and somatic and fetal cells.
8.7.3.1 Case III: Genotoxic Impurity
Viracept® (nelfinavir mesylate) is an HIV protease inhibitor marketed in Europe by Roche. Certain critical GMP deficiencies in the manufactur- ing process led to contamination of the active substance, which seriously threatened safety. A reaction between residual ethanol and methane sulfonic acid (MSA) counter ions resulted in the formation of MSA ethyl ester or ethylmethane sulfonate (EMS), which was found in unexpectedly high lev- els in the drug product. The marketing authorization holder had identified the presence of the contaminant ethyl mediate in some batches of nelfinavir mesilate (the active substance) in a follow-up investigation when patients complained about a “strange smell” and one adverse drug report of nausea and vomiting. EMS is known to be genotoxic, carcinogenic, and teratogenic in animals. Following investigations, it was discovered that vaporized ethanol was possibly transported through the piping connections of pipes meant for ethanol and nitrogen to the hold tank containing MSA in the final produc- tion step. An impurity contained in the MSA named methyl methanesul- fonate (MMS) slowly transformed into EMS through a transesterification reaction; this reaction could be accelerated by an excess of ethanol.
Pharmaceutical Formulation and Manufacturing Development: Strategies and Issues 183
The European Medicines Agency (EMA) suspended marketing of the drug in June 2007. But the EU marketing authorization was reinstated in October 2007, when the issue was resolved. Stringent toxicity studies were required to support the safety profile [29]. EMEA later requested evaluation of sulfonic esters in all marketed products (December 2008).
8.7.4 Issues of Repetitive Cycle in Drug Manufacturing
Procedural barriers influence continuous process improvement in manufac- turing and this aspect of manufacturing is tightly regulated. Moreover, there are increasing difficulties in altering the regulator-approved procedures that have been validated. Manufacturing techniques that are outdated lead to failed predistribution testing – an inability to separate the “wheat from the chaff ”. Implementing modernized technology and processes that have been constrained by the FDA regulatory systems is difficult when earlier proce- dures have been well characterized and validated, and thus there has been series of violations associated with increasing complexity in the hard-to- comply FDA demands. These contribute to major problems in the health- care system, which include recalls, related contamination events, and drug shortages affecting both brand-name and generic products. Series of recalls are due to manufacturing-related contaminations from equipment, cross- contamination from other drug ingredients, and loose particles form equip- ment parts. New contaminants or impurities could lead to higher levels of contamination, which could lead to the termination of the entire program.
These problems have contributed to drug shortages that have affected the healthcare systems, the patients, society, and even the drug companies them- selves. The highly stringent regulatory oversight has also led to the closure of manufacturing plants and drug shortages, all of which account for qual- ity lapses and reduced drug supply. Is the shutdown of a plant a regulatory threat or a win situation for the FDA? Is this a credible threat?
8.7.5 Sterility Issues
Supply disruption is among the most common causes of drug shortage due to manufacturing suspense or delayed production associated with a quality problem, which typically has been connected with bacteria contamination or foreign particles in drug containers or vials. For example, penicillin, an anti-infective drug, is highly sensitizing and could lead to severe allergic reactions even at minimal levels, which might limit the manufacturing lines. Lack of extensive manufacturing lines has a resultant effect of shar- ing of lines for the manufacture of multiple drugs. This is a possible source
of cross-contamination for companies, which will have to compromise in favor of one drug [19]. Plant closures have been intuitive in response to a warning letter issued by the FDA (Figure 8.3).