Definitions and scope of quality systems in pharmaceuticals has evolved over a period of time. The “Thalidomide babies tragedy” prompted the concept of continuous or cGMP. With cGMP came into existence the concept of Quality Assurance or “Zero defect”. QA advocated that quality cannot be created at the end of processing, but has to be in-built into a product at every step of manufacturing process.
Further improvements in quality systems throughout the 1990’s and beyond brought about concepts of internal audits, documentation and validations. Y2K improved quality systems further...introduced 21CFR part 11 compliance measures. Year 2010 and beyond promises further refinement in quality systems- Quality-by-Design (QbD).
What is quality by design?
Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process.
Where to implement quality by design?
Quality by design implementation targets the following departments within a pharmaceutical company-Management, Procurement, R&D, Manufacturing, Testing, Quality control, Quality assurance, Regulatory, Logistics, Sales, Warehouse/ Supply chain including vendors facilities, CRO and CMO.
Principles of quality by design?
QbD scope assume that problems can be anticipated and their occurrence prevented by reviewing data and analyzing risks associated with operational and quality system processes and by keeping abreast of changes in scientific developments and regulatory requirements. The central goal of a quality system is the consistent production of safe and effective products and ensuring that these activities are sustainable. A robust quality system will promote process consistency by integrating effective knowledge-building mechanisms into daily
operational decisions. When fully developed and effectively managed, a QbD system will lead to consistent, predictable processes that ensure that pharmaceuticals are safe, effective, and available for the consumer.
Framework of quality by design?
Quality by design integrates quality systems and risk management approaches into its existing programs with the goal of providing the necessary framework for implementing quality by design (building in quality from the development phase and throughout a product’s life cycle), continual improvement and risk management in the drug manufacturing process and also for post development changes and optimization.
Quality risk management (governed by CAPA- corrective actions preventive actions) is a valuable component of an effective quality systems framework. Quality risk management can, for example, help guide the setting of
specifications and process parameters for drug manufacturing, assess and mitigate the risk of changing a process or specification, and determine the extent of discrepancy investigations and corrective actions.
CAPA focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence. QbD system models discuss CAPA as three separate concepts, all of which are used in this guidance:
1. Remedial correction of an identified problem.
2. Root cause analysis with corrective actions to help understand the cause of the deviation and potentially prevent recurrence of a similar problem.
3. Preventive action to avert recurrence of a similar problem.
Review outcomes typically include:
• Improvements to the quality system and related quality processes.
• Improvements to manufacturing processes and products.
• Realignment of resources.
The results of a management review would typically be recorded. Planned actions should be implemented using effective CAPA and change control procedures.
To be continued...
Can cytotoxic substances and high potency actives- api be manufacture in the same manufacturing facility on campaign basis? What's the regulatory angle?
It is important to distinguish a drug with a characteristic that poses a high occupational risk from its characteristic therapeutic effect & benefit, in short potency.
For example, a drug that increases the acceptance of a transplated organ is given to patients in high doses. However, occupational exposure of that same drug may cause birth defects in the off-spring of workers who may come into contact with it. Therefore OEL (Occupation Exposure Levels) will play a major role rather than plain potency of the api.
If one is able to establish effectiveness of manufacturing environment containment systems, waste stream management and industrial hygiene (IH) practises performed with respect to OEL, further complemented by cleaning validation data, should by far indicate compliance.
Isolation and identification of bacteria-
The isolation was done by transferring the colonies from nutrient agar plated to sterile enrichment broth media. These included MacConkeys broth (for detection of Staph.aureus) and Cetrimide broth (detection of P.aeruoginosa). The specimen tubes were incubated for 48 hours at 37 + 1 oC in inverted position for
24 hours and 507 days.
Allocation of mannitol salt agar B30-
The colonies grown on Vogel –Johnson’s medium was streak plated on sterile mannitol –salt agar medium for confirmation regarding presence/ absence of Staph. aureus . Pure staphylococcus culture ATCC 12600 was simultaneously streaked on separate plates to serve as positive control.
Further study of culture on selective media-
The colonies grown on Vogel- Johnson’s medium and MacConkeys medium were tested for Gram reactions and motility characteristics.
In order to further ensure that the organisms cultured on Vogel- Johnson’s and Mac Conkeys agar were probably E.coli, Staph. aureus or Salmonella species, the inoculums of the colonies from respective agar medium were employed in biochemical tests comprising of hydrolysis of starch, nitrate reduction, oxidase and catalase activity, liquefaction of gelatin, IMVic, Oxferm reaction etc.
The contents of this article belong to extensive laboratory work done by me to assess microbial contamination on few brands of dye and lake colors available in the market.
Marketed samples of indigo carmine, sunset yellow, erythrosine and ponceau 4R dye and their aluminum lakes. Materials used in the preparation of the lakes including aluminum hydroxide powder (batch nos. 103,374,AD3 and paste P61). Nutrient agar, Vogel-Johnson’s medium, Mac Conkeys medium, Cetrimide medium and
agar media of these and mannitol salt agar were from M/s Hi media, India. Other stains and chemicals employed were of highest purity.
Sampling, sample handling and sample condition-
All the samples obtained were powders, excepting aluminum hydroxide, which was supplied also as a paste. The samples were received in tightly closed glass bottles.
The surface of the sample container was disinfected with an aqueous mixture of 80 % alcohol v/v and 1 % v/v. The surface was dried with sterile gauze before opening and removing the contents in laminar air flow cabinet.
(I) Preparation of stock inoculums -
One-gram test sample was aseptically inoculated in 25 ml of sterile nutrient broth. The inoculated medium was kept undisturbed for about 15 minutes, to ensure complete transfer of microbes from sample to the medium. The clear supernatant liquid was then used a sample for performing the tests.
(ii) Determination of MPN by serial dilution method-
One ml of stock inoculums prepared as mentioned under (i) was diluted with 9.0 ml nutrient broth to give a dilution of 1:10. this was further serially diluted with sterile nutrient broth to give 1:100, 1:1000 and 1: 10000
The labeled tubes were inoculated at 37 + 1 deg.C for 24- 48 hours and 5-7 days after which they were observed for the presence or absence of growth. The tube in which the growth was not clear from appearance was sub-cultured into fresh sterile nutrient broth tubes (0.1 ml was inoculated into 10 ml sterile nutrient broth). Negative and positive (E.coli ATCC 11775) control was maintained to test the effectiveness of sterilization procedures and growth promoting property of the nutrient media respectively.
(iii) Determination of bacterial count by plate count technique-
The stock inoculums prepared under (i) was serially diluted with sterile physiological saline to give 1:10,1:100,1:1000,1:10000 ,1:1,00,000 ,1: 10,00,000 dilutions. Depending on the MPN count values determined above in (1) 1.0 ml of the last two dilutions of the sample showing growth were pour plated using 15.0 ml of sterile nutrient agar. The plates were then incubated at 37 + 1 oC for 24 hours and 5-7 days and the MPN values were determined.
(iv) Detection of fungi-
One ml of the stock inoculums mentioned under (i) was added to 90 ml of Saborauds broth. Positive control (Candida albicans ATCC) and negative controls were maintained side by side. The tubes were incubated at room temperature (RT) for a period of 7-15 days.
In the next chapter, we shall discuss further on the experimental and isolation procedures of the microbes.
With the advent of out-sourcing of pharmaceutical products especially by Americas and the western world, pharma products have to meet international standards. This is not possible if quality is built into the product all the way through its trajectory from birth i.e. production development till marketing and administration to patients.
Therefore, all materials that get into a pharmaceutical product need to be closely scrutinized for its quality aspects. A commonly used excipients in formulation is color. Although, the percentages of color used in pharma products is quite low, the effect of color on formulation stability or ability of coloring ingredient for destabilizing products is well known.
Presence of microorganisms in large numbers in drugs and cosmetics preparations is undesirable since it may lead to spoilage of products. The product can change in color, consistency or manifest visible growth.
Furthermore, presence of microbial contaminants would constitute a potential hazard to public health although reports on contaminated cosmetics are rare.
A critical component involved in color stability is the microbial load. Some preliminary work on microbial contamination in cosmetics has been reported absent twelve years back from this laboratory. The earlier work in this field has been reported by Doren , Woodward , Riger , Wederburn, Kalings and Bruck .
Various sources of contamination by microorganisms have been enumerated . Raw materials are likely sources of microbial contamination and should be examined microbiologically on a routine basis. Even IP, BP and USP have recognized this fact and have set standards for total number of aerobic bacteria in a variety of products for e.g. gelatin, aluminum hydroxide gel etc. A published report by FIP working party indicated presence of high levels of microorganism not only in substances of animal and vegetable origin but also of synthetic or purified
substances including talc, kaolin, vitamins, lactose etc.
Dye colors and their lakes used for improving the elegance of the medicines and cosmetic products could become a potential source of microbial contamination in these formulations. Although the colorants are evaluated for their toxicity, their safety as regards the microbial contamination has attracted very little
attention of the regulatory authorities. The methods for evaluation of medicinal preparations are given in official compendia while those for cosmetic preparations have been adequately described by Lucas (Ref 9-12).
With this background and the fact that, the regulatory authorities might include the limits of microbes in colorants work on lakes manufactured by one company has been undertaken. The contents of the case study disclosed here is authentic. This article is published here in to give an update of our research findings to the scientific community at large with out compromising in any way the confidentiality of the matter with all associated with this work.
Results and Discussion:
Mass, IR spectral data and DSC thermo gram indicated that the pseudoephedrine test sample had high purity and compared well with the reference standard.
Under the chromatographic conditions described, the migration distance obtained in the case of both the reference as well as the test samples of pseudoephedrine hydrochloride was 34.0 mm (Rt – 0.41). the reference standard sample showed a single band. The test for selectivity employing mixture of pseudoephedrine HCl and phenylephrine showed sharp separation of HPTLC plate in the solvent system containing formic acid as mentioned earlier and compared well with the respective reference standard. The migration distance of
pseudoephedrine HCl and phenylephrine were 34.0 mm (Rt – 0.41). and 51.0 mm (Rt – 0.62). respectively.
Observation on the limits of detection and quantification, selectivity, linear range and ruggedness of the proposed method were as follows-
Limit of detection (μg) 5
Limit of quantification (μg) 10
Linear range (μg), regression coefficient, r= 0.999 35-140
Sensitivity (units) 11.2
Ruggedness (%CV) between analysts 1.224
Ruggedness (%CV) between laboratories 2.32
Comparing the accuracies (%CV calculated over the linear range) of the HPLC and HPTLC method, It was found that the accuracy of the former was 1.362 units, while that of the latter was 3.002 units.
Application to stability studies-
The results of the stability studies indicated that there was probably no interference of degradation products during the assay. The degradation products however, were not identified since the reference standards for the same were not available.
A simple, selective and rugged HPTLC method has been developed and validated for determining pseudoephedrine HCl powder. The proposed method is comparable to the HPLC method (reported earlier in the literature). The HPTLC method can be applied for studying the stability of the pseudoephedrine HCl and sulphate samples stored under stress conditions of temperature and humidity. The method further needs to be tried for the analysis of pseudoephedrine in solid and liquid dosage forms.