List of whole cell pertussis vaccine manufacturers or distributors.
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However, it also represents a significant disease burden in older children, adolescents, and adults [1]. The first pertussis vaccine was developed in 1926 [2] but has only been available for large-scale administration since the middle of the last century. Today, more efficacious vaccines based on key antigens of pertussis have been developed and are available for providing global coverage in vaccination programs [3]. These vaccines are included on the World Health Organization (WHO) Model List of Essential Medicines, as one of the most effective and safe medicines needed in a healthcare system [4]. Nevertheless, the disease is still not under control and today is considered one of the most prevalent vaccine-preventable childhood diseases. The World Health Organization (WHO) records close to 160,700 pertussis-related deaths in children younger than 5 years in 2014 and more than 24.1 million yearly pertussis cases worldwide [5]. Since the 1950s, the incidence and the numbers of pertussis-linked deaths have declined dramatically and reached its lowest point in several countries in the late 1970s, which showed the effectiveness of mass vaccination programs against pertussis. Prior to their implementation, the reported incidence of the disease was as high as 150 cases per 100,000 persons, which was most likely a vast underestimation even in countries like the USA [6]. More recently, the number of cases and associated deaths has again increased in several industrialized countries, reflecting a shortcoming in current vaccination strategies.
Two types of pertussis vaccines (PVs) are currently available: the first-generation whole-cell vaccines (wPV) and the more recent acellular vaccines (aPVs). While the efficacy of wPV (Table 1) has been demonstrated to be ≥94% after three administrations [7], the occurrence of adverse local and systemic events along with difficulties in production consistency leads to the development of aPVs in the 1980s, currently composed of one to five purified key antigens (Table 2). All available aPVs are combined with tetanus and diphtheria toxoids. Several are also formulated with hepatitis B, inactivated polio, and Haemophilus influenza B polysaccharide [8]. The aPVs clearly have an improved safety profile over wPV, and their short-term efficacy after three administrations was estimated to be 67–70% up to 84%, even those containing three or five B. pertussis components [8]. This value was recently confirmed in a systematic review of meta-analysis data focusing on the short-term protective effect of currently available childhood pertussis vaccines [9]. Because of their improved safety profiles and similar efficacies, most developed countries have replaced wPV with an aPV. Globally, wPVs are still the most used vaccines due the higher cost of aPVs, which are difficult to afford in resource-poor countries.
List of whole cell pertussis vaccine manufacturers or distributors.
Name of aPVs | Composition1 | Manufacturers/Distributer |
---|---|---|
2Acel-Imune | (PT, FHA, PRN, FIM) +DT+TT | Wyeth Pharmaceutics (USA) |
2Acelluvax (Triacelluvax) | (PT, FHA, PRN) +DT+TT | Chiron Vaccines (USA) |
3Adacel | (PT, FHA, PRN, FIM) +DT+TT | Sanofi Pasteur |
4Boostrix-3 | (PT, FHA, PRN) +DT+TT | Sanofi Pasteur |
BSc-1 | (PT) | Biocine Sclavo |
CLL-3F2 | (PT, FHA, FIM) | Sanofi Pasteur (Canada) |
Certiva | (PT)+DT+TT | Baxter Laboratory |
Daptacel (Tripacel) | (PT, FHA, PRN, FIM) +DT+TT | Sanofi Pasteur |
5DTaP-HB-IPV-Hib | PT, FHA, PRN, FIM) +DT+TT + HB + IPV + Hib | MGM Vacines Co (Merck/Sanofi) |
62HCPDT | (PT, FHA, PRN, FIM) +DT+TT | Sanofi Pasteur (Canada) |
Infanrix | (PT, FHA, PRN) + DT+TT | Glaxo Smith Klein (Rixensant, Belgium) |
7JNIM-7 | (PT) | Japan Nat Inst of Healthy |
LPB-3P | (PT, FHA, PRN) | Wyeth Lederle Vaccines and Pediatric (Germany) |
MIch-2 | (PT, FHA) | Michigan Department of Public Health |
8NIH-6 | (PT, FHA) | Japan Nat Inst of Healthy |
9Pentavac | (PT, FHA, PRN, FIM) +DT+TT + HB + IPV + Hib | Sanofi Pasteur (France) |
Por-3F2 | (PT, FHA, FIM) | Speywood (Porton) Pharmaceuticals |
10Repevax | (PT, FHA, PRN, FIM) +DT+TT + IPV | Sanofi Pasteur |
SSVI-1 | (PT) | Swiss Serum and Vaccine Institute |
11SKB-2 | PT, FHA) +DT+TT | SmithKline Beecham Biologicals |
Triavax | (PT, FHA) +DT+TT | Sanofi Pasteur (France) |
Tripedia | (PT, FHA) +DT+TT | Sanofi Pasteur (USA) |
Source and composition of acellular pertussis vaccines studied and producers.
Quantitative difference can be found in the aPV compounds formulations.
No longer available (as of 2013).
A 3-in-1 vaccine, differ from Infanrix by containing reduced quantities of PT (8 μg) + FHA (8 μg) + PRN (2,5 μg) + DT (2.5 lf) + TT (5lf). Licensed for use in person with 4 yr age or older. In the USA 10-60 yr older.
A 3-in-1 vaccine approved for individuals aged ≥10 yr including those aged ≥65 yr.
The 6-in-1 vaccine is given to babies as a series of 3 doses. The first dose is given at 2 months of age, the second at 4 months, and the third at 6 months. The vaccine is given at the same time as other childhood immunizations.
Used in Pentacel and Pediacel.
HCPDT is the “hybrid” formulation of Tripacel, evaluated in 1993 Stockholm trial.
JNIH-6 and 7 were the aPV used in the 1986 Swedish trial.
The 5-in-1 vaccine was used in the UK for many years. In late September 2017 the UK replaced it with a 6-in-1 vaccine for all babies born on or after 1st August 2017. Both vaccines give protection against diphtheria, tetanus, whooping cough (pertussis), polio and Hib disease (Haemophilus influenzae type b).
A 3-in1 vaccine indicated for persons from 3 years of age as a booster following primary immunizations.
SKB-2 was an experimental two-company DTaP evaluated in the 1992 Stockholm trial.
Abbreviations: PT, pertussis toxin; FHA, phytohemagglutinin; PRN, pertactin; FIM, fimbriae (mixture of FIM-2 and FIM-3); TT, tetanus toxoid; DT, diphtheria toxoid, HB, Hepatitis B; IPV, Inactived Polio; Hib, Haemophilus influenzae type b.
Although the vaccines together have saved millions of people since its introduction, it has been estimated that their effectiveness appears to decrease between 2 and 10% per year [1, 10]. This rate of decrease has been observed in countries that continue to administer wPV. Yet, it has become apparent that the immunity induced by aPV declines substantially faster than that induced by wPV [11, 12], which led the WHO to recommend that countries considering a switch from wPV to aPV should expect further guidance [4]. Multiple studies, both epidemiological and serological, have confirmed that immunity wanes rapidly after the aPV booster at age 4–6 years and the preadolescent dose at age 10–12 years [13, 14, 15, 16, 17, 18]. Nonetheless, it appears that the waning immunity induced by aPV, or wPV, is not the only reason for the observed resurgence in pertussis infections.
Another possible mechanism is asymptomatic transmission. Mathematical modeling of the incidence rates of pertussis in the USA and UK supports a role for undetectable transmission in the recent increase cases [19]. The potential for an essentially silent transmission is also supported by observations in a baboon model recently developed for studying B. pertussis infections. Vaccinations with aPV did not prevent transmission of B. pertussis. Virulent B. pertussis continued to establish infections in animals vaccinated with either aPV or wPV, even though both vaccines protected against disease. A major difference observed between the two vaccines was that infections cleared more rapidly in wPV-vaccinated baboons [20]. All vaccinated animals showed a lower total bacterial load compared to naïve animals suggesting that both vaccines have a positive impact to limit the progression of an infection. Yet, it appears that this impact may not be sufficient to control the circulation of B. pertussis within a population and could lead to the generation of vaccine escape mutants, which have indeed been observed in several countries where aPV is in use. A likely explanation is the observed increase in the isolation of strains not producing pertactin, due to selective pressure [21]. Conversely, there is no apparent major difference in the pathogenesis of whooping cough in children infected with pertactin-deficient strains compared to pertactin-producing strains. This indicates that pertactin is not required for infection by B. pertussis or for the development of the disease, suggesting a role of pertactin in the immune response following vaccination.
In contrast to vaccination with either aPV or wPV, a natural infection by B. pertussis is able to induce sterilizing immunity in baboons [20]. This fact is intriguing since studies in human have shown that infection-induced immunity is longer lived than vaccine-induced immunity [22], although probably not lifelong as reinfections have been reported to occur. While the second attacks are very rare, they are usually much milder than the primary infections [23]. Since B. pertussis is strictly a mucosal pathogen, it is conceivable that its restricted localization could influence the immunity induced from a natural infection. Although the protective role of mucosal immunity has so far attracted little attention, it may contribute to the differences observed between the protection obtained by a vaccine and a natural infection. These observations suggest that a vaccination approach that more closely mimics a natural infection without resulting in disease may be more successful to ultimately control pertussis.
Such a vaccine is currently under development based on a live attenuated B. pertussis strain. Named BPZE1, it has been genetically modified to affect the activity of three different toxins such that they are absent, inactive, or minimally active [24]. This strain has been documented to be safe in preclinical models and genetically stable over at least 1 year of continuous passaging in vitro and in vivo in mice [25]. It can induce a strong protection against challenge infections after a single intranasal administration, which lasted at least for up to 1 year. This contrasts with the protection conferred by aPV that can begin to wane after only 6 months. The strain BPZE1 has successfully completed a Phase I clinical trial that showed its safety profile in young male volunteers with a single intranasal dose of up to 107 colony-forming units suspended in 100 μl. This trial also showed that BPZE1 can transiently colonize the human nasopharynx and induce B. pertussis-specific antibody responses in all colonized individuals. At 6 months, follow-up studies measured antibody titers against all antigens tested to be at least at the same level as detected at 1 month postvaccination. One concern with the trail was the observation that not all subjects showed colonization by BPZE1, even at the highest dose tested, since colonization was found to be essential for the induction of an immune response. A possible reason of the absence of colonization in some individuals may have been their prior contact with wild-type B. pertussis, which could have prevented a response to the vaccine. Consistent with this hypothesis is the detection of preexisting antibody titers in the non-colonized individuals that were significantly higher than the pre-vaccination titers of individuals that displayed colonization, especially against pertactin. Additional studies are needed to test the influence of a prior exposure to wild-type B. pertussis on BPZE1 colonization and to eliminate the possibility for a previously imperceptible subclinical disease. New clinical trials are in progress to test the hypothesis that the presence of preexisting antibodies prevents colonization by the vaccine strain and to determine if their activity can be neutralized by increasing the vaccine dosage.
Realistically, it would require many more years of research and regulatory approval before a new pertussis vaccine could be available for general use. In the interim, efforts are being made to optimize the application of current vaccines. A promising observation is the protection afforded to newborns, less than 2 months of age, from the immunization of their mothers with aPV during the 28–38th week of gestation. In a recent pertussis outbreak in the UK, the effectiveness of this vaccination schedule was shown to be greater than 90% [26]. Several countries have now made recommendations for providing aPV during pregnancy. However, many issues remain unresolved. For example, the impact of maternal immunization on the immune responses in infants following their primary vaccination is unclear. Several studies have observed a reduction in the primary antibody response to B. pertussis antigens following a maternal vaccination [27]. Another issue is the observation that the adoptive caring immunity is effective to prevent disease but does not prevent pertussis infections in neonates [28]. This suggests that the maternal levels of preexisting pertussis-specific antibodies cannot transfer complete protection against infection. The maternal immune system can be activated in response to pertussis and generates a recall response from memory B cells that increases the levels of milk IgA, but the clinical relevance remains to be determined. Lastly, in a mouse model, challenge studies also have shown that antibodies resulting from maternal vaccinations interfere with the functionality of antibodies induced from a subsequent vaccination [29].
In 2008, there was an estimated incidence of 16 million cases of pertussis infection worldwide that resulted in approximately 195,000 children deaths, making pertussis one of the leading causes of vaccine-preventable deaths in children under 5 years of age [30, 31]. Most of pertussis deaths occur in developing countries. However, pertussis has not only persisted in countries with high vaccination coverage but has resurged with a number of epidemic episodes being recorded [32, 33, 34]. The resurgence of pertussis as a deadly childhood disease is a major public health concern that reflects changes in its epidemiology but is also affected by a growing attitude among parents to delay or even refuse vaccination of their children, which highlights the urgent need for new integrated approaches to control the spread and impact of whooping cough. Several explanations have been presented to enlighten the resurgence of pertussis disease over the past few decades in which most of them is associated with the aPVs currently in use: (i) the decrease of vaccine effectiveness over time (declining immunity) [35, 36], (ii) the selection of mutants that can escape the immunity induced by a vaccine [37, 38], and/or (iii) failure of the vaccine to induce sterilizing immunity to the pathogen that avoids transmission [20]. However, perhaps the most significant contributing factor is our relative lack of understanding the basics of pertussis infection, immunity, and disease. We are still unsure of which specific immune responses are protective against B. pertussis infection and disease in humans and how to elicit protective responses through vaccination.
To address the resurgence, new vaccination strategies have been explored such as the “cocooning strategy” and maternal immunization. Cocooning refers to the vaccination of mothers and others with direct contact to newborns and infants. Cost-effective cocooning would be difficult to implement since a successful program requires a very high number of contacts be vaccinated to attain a significant impact on the incidence of severe infant pertussis [39]. Currently, there is a growing evidence for effectiveness of immunization of women during pregnancy rather than during the immediate postpartum period. This approach has been found to be more cost-effective than cocooning with a level of vaccine effectiveness against infant deaths that reach an estimated 95% [27]. Alongside the vaccination of contacts, an alternative option under consideration is to advance the vaccination schedule for newborns to 6–8 weeks of age. However, this approach still does not provide protection to infants during their most susceptible period for potentially deadly pertussis infections. A missing element to refinements in the application of available vaccines is an improved surveillance for pertussis. Improvements in the detection of infections and the immune response can positively contribute to evaluations on vaccine efficacy that will help advance our understanding of performance and duration of a pertussis vaccine to provide protection in the field.
Since the 1950s, the toxicity of traditional wPV has been associated with the presence of lipopolysaccharides (LPS), the major constituents of the bacterial outer membranes. To improve on traditional wPVs, the Butantan Institute in Brazil recently produced a wPV with reduced quantities of LPS that removed ≥80% of the endotoxin-related toxicity in comparison to traditional wPV production methods using a chemical extraction of lipo-oligosaccharide (LOS) from the outer membrane. The process maintained the main protective immunogens as well as the integrity of the bacteria in the vaccine [40]. A major challenge over the next few years will be the implementation of a reproducible process that can produce consistent lots under good manufacturing practice conditions.
In recent years, extensive research efforts have elucidated that natural infections and immunizations with wPVs predominantly induce IFN-γ-secreting T-helper 1 cells (Th1) and IL-17-secreting Th17 cells [41, 42, 43, 44]. By contrast, it has been shown that aPVs induce a qualitatively different immune response, characterized by the induction of Th2 immunity [39, 43, 44, 45]. This difference in the immune response, along with the chemical inactivation of the pertussis toxin antigen in aPVs, may account for the apparent lack of aPV protection against colonization by subsequent B. pertussis infections and suboptimal T-cell priming that has been observed as a reduction in the efficiency for the generation of an immune memory repertoire.
Since current aPVs mainly elicit a Th2 response, several solutions have been proposed to improve the Th1/Th17 responses. One possibility is to combine these vaccines with Th1-driving adjuvants, at least for the priming doses [46, 51]. The development of such a candidate vaccine based on a single-immunization platform consisting of three immune stimulators is in progress [47], namely, (i) host defense peptides, (ii) polyphosphazenes (a family of inorganic molecular hybrid polymers based on a phosphorus-nitrogen backbone substituted with organic side groups with very diverse properties), and (iii) the synthetic oligonucleotides containing CpG-ODN (oligodeoxynucleotides) combined with poly(I:C), (polyinosinic-polycytidylic acid) an agonists of Toll-like receptor 9 (TLR9). This last immune stimulatory compound associated with dacarbazine, a therapeutic agent, has been successfully used to promote antitumor immunity [48].
In the case of pertussis, the inclusion of these immune stimulators resulted in a humoral immune response from a single application in neonatal mice and pigs that was 100- to 1000-fold stronger than a licensed aPV [47]. The onset of immunity occurred more quickly with a predominantly Th1 response. Importantly, immunity persisted for more than 2 years and appeared to be highly effective even in the presence of maternal antibodies. To address the contribution of chemically inactivating pertussis toxin to vaccine performance, a strain of B. pertussis was engineered as a source for genetically detoxified Ptx for the formulation of a new aPV. In Thai adolescents, its safety was like Adacel, a trivalent aPV combined with diphtheria and tetanus compounds produced by Sanofi Pasteur (see Table 2) with an improved induction of neutralizing antibodies against PTx [47].
Substantial evidence has been accumulated in the last 2 years that immunity induced by aPVs is much shorter lived than immunity induced by wPV [10]. Additionally, using refined techniques of peptide microarray, it has been demonstrated that qualitative differences within the humoral response of individuals vaccinated with wPV and aPVs exist. Using a microarray technique, it was shown that animals immunized with wPV recognize qualitatively a major number of B epitopes in the PTx than mice immunized with aPV [49]. Another study using a similar approach compared the recognition pattern of sera from children immunized with different pertussis vaccines (17 B. pertussis proteins) and concluded that 11% of the individuals displayed a private humoral response [50]. All these studies are important to guide the rational development of new vaccines.
While adults and adolescents normally only experience mild symptoms from a pertussis infection, they are the usual source of infection for neonates, and adoptive maternal immunity does not appear to prevent pertussis in neonates. In a study that compared the specific immune response in mothers of neonates diagnosed with pertussis and mothers of control children [28], preexisting pertussis-specific antibodies were insufficient for protection suggesting that memory B cells play a major role in the adult defense, which is not transferred to neonates. To provide newborns with protection, a new approach would be required, but to change the vaccine given to infants in the first 2 years of life is a discouraging proposition. It would involve a large data set for safety evaluation. Also, the pertussis vaccine is often combined into a multivalent formula with components against other pathogens. Any change directed at improving effectiveness against pertussis would require a recertification process that would impact a wide spectrum of vaccines currently on the market.
More importantly, it would be unethical to conduct formal efficacy studies for new vaccines/formulations that included a non-vaccinated control group. Considering the epidemiological and serological studies that show a rapid decline in immunity after the recommended aPV boosters at ages 4–6 and 10–12 years [13, 15, 16, 18], an intensive focus is being given on the booster vaccines given to preschool-age children and adolescents. However, even for a new booster vaccine, the regulatory pathway is unclear. A classical efficacy study would have to compare a new vaccine with a currently accepted one to show non-inferiority or superiority. Such studies would be expensive and require a long evaluation period considering that the current vaccines are effective for the first couple of years after administration.
Ideally, licensing authorities could present new approaches to evaluate the efficacy of a new vaccine. Alternatives include a greater reliance on the use of protection data obtained from animal studies [52]. The newly developed baboon model could provide in-depth serological data on the levels and duration of antibody titers, which can be verified in smaller human challenge studies using circulating strains of B. pertussis. Safety profiles could also be generated from fewer participants if modifications simply involve an update in the components with newer inactivation methods, such as genetic modifications. However, the greatest obstacle is most likely to recruit manufacturers to participate in the development of a new pertussis vaccine or booster. After the tremendous effort and expenditure invested to launch the aPVs along with shifting priorities to new pathogens, major manufacturers are resistant to shouldering multiple and simultaneous clinical development programs [52]. Physicians and government health agencies will be critical to creating a new demand. Assistance from academia and science funding agencies could assist vaccine development by conducting basic research on the pathogenesis and immunology of pertussis along with preliminary clinical trials [52]. All of this implies an enormous effort, but a new pertussis vaccine is needed. It is unethical to continue to allow a vaccine-preventable disease to be incompletely controlled, especially one that prejudices the very young people and disproportionately in less developed countries.
Since the resurgence of pertussis infection, several studies have shown that the main source of infections in newborns and infants involved close-contact persons, mostly family members [53, 54]. In the first attempt to reduce the incidence of pertussis infections, indirect protection for the reduction of transmission rates was favored, the so-called cocooning strategy. In response, some countries adapted their national immunization guidelines [53, 54, 55]. Another study focused on the influence of vaccination rates among siblings and vaccination rates among mothers showed that the provided protection rates are comparable [56, 57]. In contrast, a recent study on the effect of cocooning infants younger than 6 months of age did not detect any reduction in pertussis cases [57]. Besides that, it is not yet clear and has created some controversy if cocoon strategies are cost-effective or even prevent infections [38, 58]. Even in the absence of definitive proof, it is still advisable for recent mothers to know their immunization status as well as those of all potentially close-contact individuals, all of whom can play a critical role in the potential transmission of pertussis to a newborn.
Another means to reduce the rate of pertussis transmission to neonates and young infants is the practice of providing pertussis vaccinations during pregnancy. This has become an important strategy in many countries in the absence of vaccines licensed for use before the age of 6 weeks and unknown effectiveness of cocooning strategies [53, 59, 60, 61]. The observation of the transplacental transfer of maternal anti-pertussis antibodies to the fetus led health authorities to first recommend the use of pertussis vaccinations during pregnancy in 2011 [62, 63, 64]. In the USA, a maternal vaccination was first recommended after gestational week 20 that was later shifted to a window between weeks 27 and 36 [65]. This recommendation has been adopted by both Switzerland and the UK [64].
Early studies showed that vaccination with Tdap vaccines during gestational week 27–30 + 6 was associated with the highest levels of IgG in umbilical cord blood when compared to vaccination beyond gestational week 31 [59], according to one of the most potent virulence factors of pertussis PTx. A recent study supports these data by showing that the maternal vaccination with Tdap early in the second trimester significantly increased neonatal antibodies at birth in comparison with neonates born from mothers vaccinated in the third trimester [61]. All in all, the antenatal vaccination campaign in the UK achieved a vaccine coverage of 60% with >90% effectiveness [66, 67]. A UK study conducted after initiating maternal vaccinations identified a large reduction in the number of confirmed cases of pertussis infection reported as the cause for a hospital admission that was especially notable for infants younger than 3 months of age [66].
From this campaign, the question arose as to whether a vaccination early in pregnancy might adversely affect the immune response in an infant to vaccinations after birth. Some studies showed that antibody concentrations at birth did not interfere with the immune response to further immunizations after birth [68]. However, it is known that maternally derived antibodies can interfere with the immune response in an infant vaccinated with the same vaccine [68], which was detected after DTaP1 (administered to children under 7 years of age) vaccination [69]. Maternal antibodies were also shown to interfere with the antibody response to the primary vaccination administered during infancy to children born to Tdap1 (administered to older children and adults)-vaccinated mothers [62, 70]. Interestingly, a mouse model showed that the vaccination of infant mice reduced the protective functions of maternally derived antibodies in vitro and in vivo [29]. A study that focused on vaccinations with Repevax, a five component aPV combined with tetanus, low-dose diphtheria, and inactivated polio vaccine (Sanofi Pasteur), detected a significant attenuation of pertussis antibodies in infants whose mothers were vaccinated with Repevax during pregnancy [71]. Together with the diminished protection afforded by aPVs, recent findings suggest that the efficacy of current vaccines should be maximized by prenatal vaccination followed by boosting. It is important to continue studies to determine the functionality of maternal antibodies resulting from vaccinations during pregnancy and infant antibodies generated from subsequent vaccinations to better understand the potential for cross interference to design alternative vaccination strategies.
It is irrefutable that the worldwide incidence of severe pertussis cases is rising. Nearly 90% of all instances of deaths caused by pertussis occur in infants younger than 4 months of age and are caused by fatal pertussis pneumonia due to PTx activity [72], which highlights the need to inhibit PTx during an acute infection. Over the past few years, the scientific community has responded by initiating studies focused on a better understanding of virulence factors, like PTx, transmission dynamics, and host immune reactions, which can provide a foundation for the generation of a new vaccine but can also guide improvements in the use of current vaccines. It is clear that a control of pertussis requires a durable protection against disease and disruption of transmission. The two types of vaccines available, wPV and aPV, are effective in preventing the disease, but the immunity developed by each wane over time, even more rapidly with aPV, which should encourage countries in which wPV is still in use, not to switch to aPV. Further, transmission from vaccinated individuals is possible since B. pertussis can still colonize their respiratory tracts. Improvements to both types are in development, but it will be several years before their widespread use. In the interim, expansions in the use of the current vaccines have been proposed. Cocoon vaccination programs, which are controversial in their effectiveness, rely on generating herd immunity to protect young infants by vaccinating individuals with close contact. In contrast, immunization with aPV during pregnancy can reduce the incidence of severe and deadly pertussis in neonates. However, there are concerns that the antibodies raised from the maternal immunization can interfere with the immune response in the child to their primary vaccination. All approaches under development would benefit from a more detailed surveillance program to determine the rates of symptomatic and asymptomatic infections as well as an examination of the genetic diversity of B. pertussis strains in circulation to better understand methods to prevent the impacts of infection.
SGS received support from the Brazilian Council for Scientific Research (CNPq-no 467.488.2014-2), Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State (FAPERJ no E-26 110.198-13), and Higher Education Coordination for the Improvement (CAPES-no 2919-2010).
The authors declare no conflict of interest.
Tablets are the most preferred dosage form with respect to patient acceptability, flexibility in dose adjustment, easy manufacturing, and better stability [1, 2]. Irrespective of the nature of the drug and its manufacturing technique, tablets should meet some strict requirements in terms of mechanical strength, disintegration, and drug release [3, 4, 5]. A variety of techniques are available for tablet preparation among which direct compression is mostly preferred due to simplicity, cost-effectiveness, and less number of involved steps [6, 7]. However it can be applied only to the powder blend having optimum rheological characteristics, mechanical strength, and disintegration behavior, i.e., the powder blend should flow efficiently, and the resultant tablet should have sufficient mechanical strength with acceptable disintegration behavior [8, 9, 10]. All these characteristics are interlinked, and usually improvement of one characteristic can adversely affect the other. Hit and trial is the mostly applied method for optimization of powder characteristics which is laborious and material consuming. Optimization of powder blend is carried out, mostly, in the last stage of formulation development (following pre-formulation studies). Usual reported time for formulation development is in the range of 14–20 days, which can further extend in certain cases. There was a need for a technique that can avoid the experimentation for optimization of powder characteristics and help in excipient selection, i.e., select proper quantity of an excipient with desired characteristics. SeDeM-ODT expert system is a pre-formulation tool and has solved most of the problems associated with material characterization at pre-formulation level. SeDeM-ODT expert system minimizes experimentation and facilitates the process of formulation development by helping in excipient selection (in terms of desired characteristics and required quantity).
SeDeM-ODT expert system is novel pre-formulation technique applied for development of a solid dosage form (tablets) by direct compression technology [11]. The system characterizes powder substance on the basis of various parameters related to flow, compressibility, and disintegration behavior. Physical profile of powder substance is developed, suggesting its suitability for direct compression and bucco-dispersibility [12, 13]. SeDeM expert system can be segmented into the following:
SeDeM expert system: It determines suitability of the powder substance for direct compression only [11, 13]. That is, the system characterizes powder substance with respect to its rheological characteristics and compressibility.
SeDeM-ODT expert system: It is the newest version of SeDeM expert system and characterizes the powder substances with respect to rheological characteristics, compressibility, and disintegration behavior, simultaneously [14]. Three extra parameters related to characterization of disintegration behavior are included in the SeDeM-ODT expert system.
The SeDeM-ODT expert system has been introduced with the aim of designing oro-dispersible tablets (ODTs) by direct compression [14]. This system is unique as it provides an oro-dispersible tablet formulation by direct compression, i.e., it links prediction of suitability of powder for direct compression and rapid disintegration of the tablets. SeDeM-ODT expert system is used for evaluation of critical quality attributes of powder substance, having an impact on the final product. Quality by Design guidelines ICH-Q8 [15] provides the basis for SeDeM-ODT expert system.
SeDeM-ODT expert system also calculates the amount of excipients with certain characteristic required for the correction of a particular property in order to make a final blend suitable for direct compression [14]. Several parameters have been selected that must be fulfilled by the formulation (excipients) to ensure successful and robust processing by direct compression technology.
On the basis of physical characteristics and functionality of the ingredients, various parameters are grouped into six factors, as follows:
Parameters included in this factor affect the size of the tablet and its ability to pile up. Results of these parameters are also used in the mathematical calculation of other indices related to powder compressibility. Parameters included in this group are:
Bulk density
Tapped density
The factor comprised of the parameters related to compressibility of powder and includes the following:
Inter-particle porosity
Carr’s index
Cohesion index
This factor governs flow ability of the powder during compression and includes the following:
Hausner ratio
Angle of repose
Flow ability
Lubricity during compression and stability of the compressed tablets are affected by the parameters included in this factor. These are the following:
Loss on drying
Hygroscopicity
This incidence factor shows the rheological properties and stability of the powder and depends upon the intrinsic moisture and hygroscopicity of the material [14]. The low value of this incidence factor shows that the product will absorb moisture from the atmosphere, worsening its rheological properties (flow and compression) and consequently altering product stability. In case of values below the acceptable limit, the following measures are taken:
Drying of material to reduce its loss on drying.
Product should be processed in a controlled environment at low humidity.
Parameters included in this factor affect the lubricity and dosage of the tablet and comprised of the following:
Particles having size below 50 μm
Homogeneity index
Parameters included in disgregability factor govern disintegration behavior of the final product and are specified for fast dispersible tablets. Parameters included in this factor are as follows:
Effervescence test
Disintegration time with disk
Disintegration time without disk
Table 1 shows the basic parameters determined according to the SeDeM-ODT expert system along with their symbols, units, and classification into different incidence factors.
Incidence factor | Parameter | Symbol | Unit | Equation | Limits | Applied factor |
---|---|---|---|---|---|---|
Dimension | Bulk density | Da | g/mL | Da = P/Va | 0–1 | 10 V |
Tapped density | Dc | g/mL | Dc = P/Vc | 0–1 | 10 V | |
Compressibility | Inter-particle porosity | Ie | — | Dc – Da/Dc × Da | 0–1.2 | 10 V/1.2 |
Carr’s index | Ic | % | 100 (Dc–Da)/Dc | 0–50 | V/5 | |
Cohesion index | Icd | N | *Experimental | 0–200 | V/20 | |
Flow ability/powder flow | Hausner ratio | IH | — | Dc/Da | 3–1 | (30–10 V)/2 |
Angle of repose | (α) | o | tan−1 (h/r) | 0–50 | 10 – (V/5) | |
Powder flow | t″ | S | Experimental | 0–20 | 10 – (V/2) | |
Lubricity/stability | Loss on drying | %HR | % | Experimental | 0–10 | 10 – V |
Hygroscopicity | %H | % | Experimental | 0–20 | 10 – (V/2) | |
Lubricity/dosage | Particles <50 | %Pf | % | Experimental | 0–50 | 10 – (V/5) |
Homogeneity index | IѲ | — | Fm/100 + ∆Fmn | 0–2 × 10−2 | 500 V | |
Disgregability | Effervescence time | DE | Min | Experimental | 0–5 | (5 – V) × 2 |
D. time with disk | DCD | Min | Experimental | 0–3 | (3 – V) × 3.333 | |
D. time without disk | DSD | Min | Experimental | 0–3 | (3 – V) × 3.333 |
Basic parameters of SeDeM-ODT expert system divided into different incidence factors.
D. time with disk: Disintegration time with disk.
D. time without disk: Disintegration time without disk.*Experimental; The parameter was determined experimentally.
To determine the suitability of powder/powder blend for direct compression and bucco-dispersibility, SeDeM-ODT expert system needs 15 parameters to be found out. The individual parameters of SeDeM-ODT expert system are determined according to their respective pharmacopoeial methods, reported methods, or calculation on the basis of other basic parameters.
Characterization of powder according to the SeDeM-ODT expert system [11, 14] involves the following:
Determination/calculation of basic parameters
Conversion of experimental values to “r” values by applying specific factors and graphical presentation of results
Calculation of various indices on the basis of “r” values
SeDeM-ODT expert system is based on 15 basic parameters [14] which are determined experimentally or calculated on the basis of other included parameters. Procedures for the determination of basic parameters are given below:
Bulk density of the powder substance is determined according to the USP using graduated cylinder method [16]. The volume of the weighed amount of powder is determined using a graduated cylinder, and the density is calculated using the following equation:
where D is the density of the powder (g/mL), m is the weight of the powder (g), and v is the volume of the powder (mL).
Tapped density of powdered material is determined according to the USP by tapping known volume of powder taken in a graduated cylinder and noting the volume reduction [16]. Tapping can be carried out manually or using mechanical tappers.
Values of bulk density and tapped density are used for the calculation of inter-particle porosity [17], using the following equation:
where Ie is the inter-particle porosity, Dc is the tapped density (g/mL), and Da is the bulk density (g/mL).
Carr’s index is calculated on the basis of tapped density and bulk density of powder [16]:
where C.I. is the Carr’s index of the powder (%), Dc is the tapped density of the powder (g/mL), and Da is the bulk density of the powder (g/mL).
Cohesion index is the crushing strength of powder compressed, preferably in an eccentric press under maximum pressure without capping and lamination [11]. The mean crushing strength is calculated for at least 10 compacts, indicating the cohesion index of the powder. The raw powder is tested for compressibility, and in case of failure, 3.5% of the following mixture is added to the mix:
Talc 2.36%
Aerosil® 200 0.14%
Magnesium stearate 1.00%
Hausner ratio is calculated from bulk density and tapped density of powder [16] according the equation given below:
where Hr is the Hausner ratio of the powder, Dc is the tapped density of the powder (g/mL), and Da is the bulk density of the powder (g/mL).
Angle of repose is determined by funnel method [18]. The test powder is allowed to flow from a glass funnel fitted at certain height, and angle of repose was determined using the equation:
where α is the angle of repose of powder (o), H is the height of the cone formed by powder (cm), and r is the radius of the base of cone formed by powder (cm).
Powder flow is determined, in accordance with the European Pharmacopeia, by measuring the time required for the powder (100 g) to flow through the orifice of a glass funnel fitted at certain height [19].
Loss on drying is determined gravimetrically according to the USP [20], using a halogen moisture analyzer. The powder (1 g) is loaded into the pan of moisture analyzer and heated for specified time at 100°C, and the value of percent loss is noted.
Hygroscopicity is measured by placing the accurately weighed amount of powder in a climatic chamber at 75 ± 5% relative humidity for 24 h at ambient temperature. The material is analyzed after 24 h for percent weight gain by reweighing [13], indicating its hygroscopicity.
Sieve shaker fitted with standard sieves of pore size 850, 600, 425, 300, and 250 μm is used for the determination of particle size distribution. The powder (100 g) is loaded on the top sieve and the sieve shaker is vibrated for 10 min. The percent amount of the powder retained over each mesh is calculated [21].
Homogeneity index is determined according to the European Pharmacopoeia [21]. The powder (100 g) is loaded to a sieve shaker fitted with sieves of 850, 500, 425, 300, 250, and 50 μm pore size, and the sieve shaker is vibrated for 10 min. The percent amount of powder retained over each sieve and that passed through a 50 μm sieve is calculated. Homogeneity index of the material is calculated using the equation mentioned below:
where I
If the percentage is higher than that calculated in the complete sieve test, it is because some of the particles become adhered to the product retained in the sieves during the grain size test, and the percentage of particles below 50 μm particles found may be lower than the true figure. The following equation (Eq. (7)) is then applied to the data obtained.
where Iθ is the relative homogeneity index and particle size homogeneity in the range of the fractions studied; Fm is the percentage of particles in the majority range; Fm − 1 is the percentage of particles in the range immediately below the majority range; Fm + 1 is the percentage of particles in the range immediately above the majority range; n is the order number of the fraction studied under a series, with respect to the major fraction; dm is the diameter of the particles in the major fraction; dm − 1 is the mean diameter of the particles in the fraction of the range immediately below the majority range; and dm + 1 is the mean diameter of the particles in the fraction of the range immediately above the majority range.
The major fraction (Fm) corresponds to the interval from 0.100 to 0.212 mm, because it falls in the middle of the other fractions of the table. This interval is calculated as the proportion in which the powder particles are found in each fraction considered in the table (as described above). Those particles located in the major fraction (Fm) in a proportion of 60% are considered to represent the minimum acceptable value of 5. The distributions of the other particles are considered to be Gaussian. The limits for the homogeneity index are set between 0 and 0.02.
Effervescence test for powder compact is determined as per official monograph [22]. The powder is compressed into tablets under maximum pressure without any capping and lamination. One tablet is placed in a beaker containing 200 mL of purified water at ambient temperature. Time taken by the tablet to disperse completely is taken as its effervescence time. Tablet is said to be dispersed completely when there is no agglomerate of the particles. In the context of SeDeM expert system, effervescence does not mean conventional acid-base reaction rather refers to dispersion of the compact in water. Effervescence time is an indicator for oro-dispersible tablets. When tablet disaggregates in less than 5 min, it is considered suitable for oral disintegration.
The powder is compressed under maximum pressure without any capping or lamination and subjected to the determination of disintegration time using USP disintegration apparatus. Disintegration time with disk is determined for at least six tablets, using de-ionized water as a medium held at 37 ± 2°C [23], and their mean is calculated (n = 6).
Results of SeDeM-ODT expert system are graphically presented as SeDeM-ODT diagram built on the basis of basic parameters. Values obtained from the experimental determination or calculations of various parameters are converted to “r” values by applying specific factors, representing radii of the diagram. The diagram is formed by connecting radius values with linear segment [13], having 0 as a minimum value, 10 as maximum value, and 5 as minimum acceptable value as shown in Figure 1. The resultant diagram indicates suitability of the material to be compressed by direct compression.
Diagrammatic presentation of (A) SeDeM-ODT and (B) SeDeM expert system. Da, bulk density; %HR, loss on drying; dc, tapped density; %H, hygroscopicity; Ie, inter-particle porosity; %Pf, particle size; IC, Carr’s index; Iθ, homogeneity index; ICd, cohesion index; DE, effervescence test; IH, Hausner ratio; DCD, disintegration time with disk; Α, angle of repose; DSD, disintegration time without disk; t″, flow ability.
Optimum mechanical strength, disintegration behavior, and rheological characteristics of powder are estimated on the basis of the following indices [11, 14] calculated using “r” values of the basic parameters.
Parametric index is the ratio of number of parameters having “r” values equal to or greater than 5 to the total number of parameters determined during the study. Parametric index was calculated using the following equation:
where I.P. is the parametric index, No. P ≥ 5 is the number of parameters with “r” values equal to or more than 5, and No. Pt is the total number of parameters determined.
Acceptability limit corresponds to a score of 5.
Parameter profile index is the average of “r” values of all the parameters determined in the study, and its acceptable limit corresponds to a score of 5.
IPP = Average of “r” value of all parameters
Good compressibility and bucco-dispersibility index (IGCB) is the product of parameter profile index and reliability factor:
where f is the reliability factor.
Inclusion of more parameters in the study will increase reliability factor. Its values are as follows:
For infinite number of parameters, f = 1 (maximum value)
For 15 parameters, f = 0.971
For 12 parameters, f = 0.952
For 08 parameters, f = 0.900
Certain limit values are set for each parameter included in SeDeM-ODT expert system on the basis of experimental results and values described in the Handbook of Pharmaceutical Excipients [24]. The rationale for establishing limit values for each parameter is given below.
Limit values of bulk density, tapped density, inter-particle porosity, and Carr’s index are calculated from the extreme values of these parameters given in the Handbook of Pharmaceutical Excipients and official monograph.
Limit of Icd is obtained by compressing powder into tablet under maximum compression force to get tablets without capping. Maximum hardness at which tablets are compressed without any capping is taken as upper limit, while 0 is taken as lower limit. 0 shows that powder cannot be compressed into tablet.
Limits for angle of repose, IH, and powder flow were set as per official monograph. Table 2 shows correlation of flow characteristics of powder to various rheological parameters on the basis of the USP [20].
Flow characteristics | Carr’s index | Hausner ratio | Angle of repose |
---|---|---|---|
Excellent | ≤10 | 1.00–1.11 | 25–30 |
Good | 11–15 | 1.12–1.18 | 31–35 |
Fair—aid not needed | 16–20 | 1.19–1.25 | 36–40 |
Passable—may hang up | 21–25 | 1.26–1.34 | 41–45 |
Poor—must agitate, vibrate | 26–31 | 1.35–1.45 | 46–55 |
Very poor | 32–37 | 1.46–1.59 | 56–65 |
Very very poor | >38 | >1.6 | >66 |
Relationship between flow characteristics and various rheological parameters.
Limits for hygroscopicity are based upon the Handbook of Pharmaceutical Excipients [24]. As per published literature [25, 26, 27], rheological and compression problems are encountered when the ratio of the fine particles exceeds 25% of the formulation.
Size distribution of the particles provided a basis for assigning limit values to homogeneity index. Table 3 indicates the size of the sieve (in mm), average particle size in each fraction, the difference in average particle size in the fraction between 0.100 and 0.212, and others.
Sieve size (mm) | Fraction | Average diameter of particles of fraction | Corresponding diameter (dm …dm ± n) | Difference of dm with major fraction |
---|---|---|---|---|
0.355–0.500 | Fm + 2 | 427 | dm + 2 | 271 |
0.212–0.355 | Fm + 1 | 283 | dm + 1 | 127 |
0.100–0.212 | Fm | 156 | dm | 0 |
0.050–0.100 | Fm −1 | 75 | dm −1 | 81 |
<0.050 | Fm −2 | 25 | dm −2 | 131 |
Particle size distribution for the determination of homogeneity index.
As the sieve range 0.100–0.212 mm falls in the middle of other factions, it corresponds to major fraction. A proportion of 60% in major fraction (Fm) is considered to be the minimum acceptable value, that is, 5. Distribution of particles into other fractions is considered to be Gaussian. Limit of homogeneity index is 0–0.02.
Initially, relative humidity was calculated based on the establishment of three intervals because the percentage relation obtained from the measurement of the humidity of the substance does not follow a linear relation with respect to the correct behavior of the dust. Humidity below 1% makes the powder too dry, and electrostatic charge is induced, which affects the rheology. Furthermore, low humidity percentages do not allow compression of the substance (moisture is necessary for compacting powders). Moreover, more than 3% moisture causes caking, in addition to favoring the adhesion to punches and dyes. Consequently, it was considered that this parameter should present optimal experimental values from 1 to 3%. Nevertheless, experience using the SeDeM diagram has demonstrated no significant variations in the results, so the previous three intervals of relative humidity can be simplified to the calculation of the parameter; thus, finally, the linear criterion of treatment of results is adopted.
The SeDeM/SeDeM-ODT expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, with the aim to determine suitability for producing tablets by direct compression technology. Additionally, this expert system also provides formulations with a minimum number of excipients and reduces the lead time during formulation development [11]. Some of the reported applications of SeDeM-ODT expert system are summarized below:
Direct compression is the most preferred technique for tablet manufacturing due to simplicity, material safety, and cost-effectiveness. Direct compression technique cannot be applied for every formulation because of some strict requirements in terms rheological characteristics and compressibility [2, 3]. Intensive experimentation is carried out to get a final powder blend suitable for direct compression. SeDeM-ODT expert system has been applied for characterization of powder to predict its suitability for direct compression. The main advantage of the expert system is to avoid extra experimentation during formulation development, reducing time and cost of formulation development [11]. Various mathematical equations are used for powder characterization, and a data base is developed which facilitates the selection of excipients having desired characteristics, at pre-formulation level.
Johny et al. applied SeDeM expert system in formulation development of oro-dispersible tablets of ibuprofen by direct compression [11]. They developed formulation after characterization of API (ibuprofen) and 21 disintegrants. Various parameters were determined for all the 21 disintegrants, according to the standard protocols, converted to “r” values by applying specific factors, and presented as SeDeM diagram (Figure 2). Deficiencies were found out for each disintegrant and were solved by proper selection of other excipients.
SeDeM diagram of various disintegrants [11].
In another study SeDeM expert system was applied for formulation development of effervescent tablets of domperidone by direct compression [28]. During the study SeDeM profile was developed for domperidone, effervescent pair (citric acid, tartaric acid, and sodium bicarbonate), and two diluents (Tablettose-80 and microcrystalline cellulose). The model drug, domperidone, was characterized, according to the established procedure, and was found deficient in dimension, compressibility, and flowability/powder flow factors. Index of good compressibility (IGC) value of domperidone was below the acceptable limit. Combination of diluents was used to get a diluent system (Figure 3) capable of compensating lower IGC value of domperidone. The developed formulations resulted in tablets fulfilling the official requirements without any stability issue with minimum experimental work.
SeDeM diagram of microcrystalline cellulose and Tablettose-80 [28].
In a study SeDeM expert system was applied for establishing a design space and determination of critical quality attributes during formulation development of captopril SR matrix by direct compression [29].
Cefuroxime axetil and paracetamol have poor rheological characteristics and compressibility. Inderbir and Pradeep [30] applied the SeDeM expert system for formulation of these two APIs by direct compression. Both the APIs were characterized following standard procedure, and excipients were selected on the basis of mathematical calculations [14].
Josep et al. developed a mathematical Equation [14] for the calculation of the amount of diluent required for the preparation of tablets by direct compression containing glucosamine salt (750 mg). Glucosamine is used in high dose (750 mg/tablet) and presents poor rheological characteristics and compressibility. Six direct compression diluents were characterized according to the SeDeM expert system, and mathematical equation was applied for the calculation of the amount of excipient to compensate the deficiencies. The theoretical model was validated by studying the calculated amounts experimentally.
where CP is the % of corrective excipient, RE is the mean-incidence radius value (compressibility) of the corrective excipient, R is the mean-incidence radius value to be obtained in the blend, RP is the mean-incidence radius value (compressibility) of the API to be corrected, and R is the 5 as 5 is the minimum value that is regarded as necessary in order to achieve good compression [14].
Figure 4 presents a strategy for the development of orally disintegrating tablets by direct compression by applying the proposed equation (Eq. (10)).
Strategy proposed by SeDeM expert system to develop orally disintegrating tables [14].
SeDeM-ODT expert system has been applied for elucidation of the effect of processing parameters on characteristics of powder substance. Amjad et al. applied SeDeM-ODT expert system for predicting the effect of taste masking on the rheological characteristics, mechanical strength, and disintegration behavior of highly water-soluble drug (Itopride HCl) [31]. Itopride HCl is a bitter-tasting, highly water-soluble drug with poor rheological characteristics. Taste of Itopride HCl was masked by water-based wet granulation technique using HPMC as taste masking polymer. Itopride HCl powder was the subjected characterization as per SeDeM-ODT expert system, before and after taste masking, and results were compared (Figure 5) to evaluate the effect on rheological characteristics, disintegration behavior, and mechanical strength. Dimension factor and flowability/powder flow factors were below the acceptable limit. Comparison of results before and after taste masking showed that taste masking significantly improved the mechanical strength and rheological characteristics and decreased the disintegration behavior of powder. It was concluded that in order to formulate by direct compression, the formulation will require large amount of disintegrant to overcome increase in mechanical strength after taste masking.
SeDeM-ODT diagram for Itopride HCl before and after taste masking [33].
Amjad [32] has applied SeDeM-ODT expert system for the optimization of process variables of roller compaction. He studied ribavirin powder and powder blend containing ribavirin and other ingredients included in granule formulation. Powder blend was compacted under varying degree of experimental conditions, and selected in the optimal conditions with better granule characteristics. He claimed that it decreased experimental work and resulted in granules suitable for compression and encapsulation.
SeDeM-ODT expert system has been applied for the determination of suitability of new powdered substances for direct compression. The powder substance may be a new API or excipients which are intended to be used in formulation of compact solid dosage forms.
Sune-Negre et al. used the SeDeM method to characterize an active product ingredient in powder form (API SX-325) and to determine whether it is suitable for direct compression [12], applying the profile to the SeDeM diagram. Twelve parameters were determined for the powdered raw material according to the standard protocols, presented as SeDeM diagram, indicating suitability of the material for direct compression. Findings of the study implied deficient rheological characteristics and poor stability. The product was declared hygroscopic on the basis of SeDeM profile and tended to capture moisture, worsening rheological characteristics and impairing its stability. Various precautionary measures were suggested for prevention of negative effects like drying of the material and tablet preparation in an environment of controlled humidity (relative humidity below 25%).
Sune-Negre et al. applied SeDeM expert system for characterization of 51 directly compressible excipients [12]. On the basis of the results, directly compressible excipients were classified into different groups with different rheological and compressibility capability, and a periodic table of directly compressible excipients was developed, as shown in Figure 6.
Correction of “compressibility” and “flowability” of APIs with excipient [12].
They showed that the best excipient for direct compression should have an index of good compressibility of 8.832 [12]. SeDeM expert system has been applied for the determination of reproducibility of various batches of pharmaceutical ingredients (APIs and excipients). Various batches were characterized according to the SeDeM expert system, and reproducibility was estimated on the basis of consistency of the results [13].
Josep et al. [33] applied SeDeM expert system for the optimization of Hausner ratio and relative humidity. The proposed optimization did not involve any conceptual change in the parameters considered or did a significant change in the results obtained compared with the previous calculation methodology initially established, meaning that the conclusion obtained by applying this method is equivalent [33].
SeDeM expert system can be applied for the determination of reproducibility of manufacturing process of pharmaceutical powder substance (API and excipients). By establishing specifications for different parameters as per SeDeM-ODT expert system, variation among different batches of a product produced by the same manufacturing process can be determined [34]. Figure 7 shows the SeDeM diagram of different batches of glucosamine sulfate, prepared by the same manufacturing procedure.
SeDeM diagram of different batches of glucosamine sulfate [35].
SeDeM-ODT expert system has been applied for the differentiation of excipients having the same chemical nature and function on the basis of physical characteristics [35]. For example, various disintegrants and diluents were characterized on the basis of the expert system [13], and the suitable one is selected for a particular formulation. Various parameters are determined according to the SeDeM expert system, deficiencies are defined, and an adequate substance can be selected to get a final blend suitable for direct compression. In a study [11] several lactose were characterized and differentiated on the basis of SeDeM expert system.
SeDeM-ODT expert system is a novel tool for the characterization of powder substances on the basis of their physical parameters. The system has been successfully applied for the determination of rheological characteristics, mechanical strength, and disintegration behavior of pharmaceutical powders (APIs and excipients) and determination of suitability for direct compression and bucco-dispersibility. SeDeM-ODT expert system facilitates the process of excipient selection and calculation of their relative proportion in oral solid dosage form. A data base can be developed for various excipients which will help in the selection of excipients having desired characteristics. It avoids extra experimentation for optimization of various characteristics of powder blend, reducing the cost and time span of formulation development process. This method characterizes the individual components of a formulation and applies a mathematical analysis to determine the exact amount of each ingredient in the final formulation. This innovative tool is consistent with the current requirements of regulatory health authorities such as the FDA and ICH, whereas data generated on the basis of the system can contribute to the concept of Quality by Design. SeDeM-ODT expert system has certain limitations, and misleading results are possible in certain cases. Suitability of material for direct compression is decided on the basis of index of good compressibility value, which is based on “r” values of the individual parameters. Substances having high “r” values will raise IGC value and vice versa. So suitability of a material should not be judged on the basis of IGC value. The incidence factor value should be considered, and outliers in “r” value of the individual factors, if present, should be properly addressed. Overall SeDeM-ODT expert system is an unmatched tool for material characterization at pre-formulation level and has significantly decreased time span and cost of pharmaceutical formulation development process.
We are thankful to Mr. Zahir Rahman (B. Pharm, M. Phil) Plant Manager, Ferozsons Laboratories Ltd., Nowshera, for his technical input and moral support.
The authors claim no conflict of interest.
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