Risk Assessment in the Manufacture Of

RISK ASSESSMENT IN THE MANUFACTURE OF

SOLID ORAL DOSAGE FORMS

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA

BY

DASARI DEEPIKA

I M.PHARM

DEPARTMENT OF PHARMACEUTICS

KARNATAKA COLLEGE OF PHARMACY

BANGALORE-560064

(2010-2011)

RAJIVGANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE,KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 /

Name of the Candidate and Address

/ DASARI DEEPIKA

Karnataka College of Pharmacy

# 33/2 Thirumenahalli
Hegde nagar main road
Bangalore-560064.
PERMANENT ADDRESS
D/O D.Narasimha Reddy,
D.No 14/119-2,opp V.C.N colony,
Sreenivasa puram, Sai kuteer road,
Proddatur - 516360,Kadapa(dist),
Andhra Pradesh.
2 /

Name of the Institution

/ Karnataka College of Pharmacy
# 33/2 Thirumenahalli
Hegde nagar main road
Bangalore-560064
3 /

Course of Study and Subject

/

Master ofPharmacy in Pharmaceutics

4 /

Date of the Admission

/ June16th 2010
5 / Title of the Topic
RISK ASSESSMENT IN THE MANUFACTURE OF SOLID ORAL DOSAGE FORMS.
6.
6.1
6.2
6.3
7.
7.1
7.2
7.3 / Brief resume of the intended work
Need for the study
Risk Management is a process consisting of well defined steps which when taken in sequence, support better decision making by contributing to a greater insight into risks and their impacts. It includes elements such as risk identification,assessment,mitigation,elimination and communication.
The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail some degree of risk. The risk to its quality is just one component of the overall risk. It is important to understand that product quality should be maintained throughout the product lifecyclesuch that the attributes that are important to the quality of the drug (medicinal) product remain consistent with those used in the clinical studies. An effective quality risk management approach can further ensure the high quality of the drug (medicinal) product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing. Additionally, use of quality risk management can improve the decision making if a quality problem arises. Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight.
The purpose of this document is to offer a systematic approach to quality risk management. It serves as a foundation or resource document that is independent of, yet supports other ICH Quality documents and complements existing quality practices, requirements, standards, and guidelines within the pharmaceutical industry and regulatory environment. It specifically provides guidance on the principles and some of the tools of quality risk management that can enable more effective and consistent risk based decisions, both by regulators and industry, regarding the quality of drug substances and drug (medicinal) products across the product lifecycle. It is not intended to create any new expectations beyond the current regulatory requirements.
It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/ or internal procedures e.g., standard operating procedures). The use of informal risk management processes (using empirical tools and/ or internal procedures) can also be considered acceptable.
The present dissertation work is to investigate the challenges involved in manufacturing of solid oral dosage forms and to identify the risks involved in it,study the impact on product quality and evaluate control measures for the betterment of process.
Review of the literature
Lawrence X Yu et al1 reported about Question based Review developed by US Food and Drug Administration office of Generic Drugs for the chemistry, Manufacturing, and Controls (CMC) evaluation of an abbreviated new drug application (ANDA). This new QbR system incorporates quality by design and implements risk-based assessment. The main benefits of this QbR system are to (1) assure product quality through design and performance-based specifications, (2) facilitate continuous improvement and reduce CMC supplements through risk assessment, (3) enhance the quality of reviews through standardised review questions, and (4) reduce CMC review time when applicants submit a QOS that addresses the QbR questions.
Steven M Short et al2defined pharmaceutical quality in terms of risk by linking production characteristics to clinical attributes.He developed a risk simulation platform that integrates population statistics, drug delivery system characteristics, dosingguidelines, patient compliance estimates, production metrics, pharmacokinetic,pharmacodynamic and invitro-invivo correlation models to investigate the impacts of manufacturing variability on clinical performance of a model extended release Theophylline solid oral dosage system.
Aditya A Wakankar et al3 determined the need for the development of a thorough and holistic extractable and leachable program based on risk assessment,review of existing literature and consolidation of industry best practices is discussed. The integration of analytical activities with health based risk assessment information into the design of an extractable-leachable program is highlighted.
Feng Qian et al4discussed the concepts and implications of the drug-polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures and proposed some practical strategies for the evaluation and development of such systems utilizing a working diagram.
Yoshiteru kato et al5studiedrisk and benefit in theapplication of near-infrared (NIR) spectroscopy to the coating process of granules to monitor the process for determining the coating end point. Cylindrical granules or spherical granules were used as core granules and were coated using a fluidized bed coating apparatus by spraying coating suspension. During the coating run, samples of granules were pulled at regular intervals and amount of talc or lactose, which were the components of the film layer, were estimated by NIR spectroscopy.
Christopher J Mortko et al6determined the most appropriate form of the active pharmaceutical ingredient for development.Slurry experiments along with analysis of physico-chemical properties were used to construct a phase diagram and select the most suitable form of active pharmaceutical ingredient for the development and the risks associated with developing this form were evaluated.
Thomas J Difeo7reported about due diligence which is a vital activity in the acquisition or the in-licensing of pharmaceutical compounds for market commercialization. Pharmaceutical productdue diligence is a detailed investigation of the chemistry,manufacturing, and controls (CMC)informationassociated with a drug product. The assessment begins with a review of the formulation. A description of the drug product qualitative/quantitative composition provides a list of all ingredients, including solvents used in the manufacture of the drug product. An understanding ofeach component’s function allows for data-drivenrisk assessment during the due diligence investigation.
Paul A Dickinson et al8introduced clinical relevance of dissolution testing in Quality by Design.How clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for biopharmaceutics classification system IIcompound. An initial clinical quality risk assessment was performed to identify the risks with an aim to assess the in vivo impact through dissolution of most relevant raw material attributes and process variables.
Chien Yueh Huang etal9determined that drug particle size distribution has a profound impact to the content uniformity in low dose solid drug products. He derived theoretically the skewness of potency distribution as a function of particle size distribution and target dose. It was demonstrated that both skewness and coefficiency of variation diverge simultaneously with inverse square root of target dose. A nomograph of the median particle size and dose that meets a 99 % pass rate was constructed for the specification of particle size or the lowest dose limit.
J G Andreou et al10 investigated the nature and extent of short term dynamic changes to dissolution within specific interactive mixtures following bending.Two micronized drugs,Nitrazepam and Flunitrazepam,were formulated into lactose based interactive mixtures containing a micronized surfactant.The dissolution rate of the drugs decreased significantly over a period of days after preparation. The dissolution was modeled using a multi-exponential equation allowing estimation of agglomeration and dissolution rate. This study emphasizes the need for improved understanding to implement a “Quality by Design” ethos to improve control and risk management over the performance and stability of these systems.
Objective of the Study
The objective of the study is as follows:

• The present work is to investigate the importance of process and risks involved in manufacturing of solid oral dosage forms and its impact on product quality
• The main aim of product quality risk management is to manufacture robust product
• This project will give an overview of manufacturing of solid oral dosage forms and importance of each and every process involved in the product manufacturing stages
• The study is on performing the risk analysis using FMEA method. The action plans will be proposed for the potential failure modes based on risk assessment

Materials and Methods
Source of Data
Review of literature from:
Journals such as

1. International journal of pharmaceutics.
2. Journal of pharmaceutical sciences.
3. Drug development and Industrial pharmacy.
4. Pharmaceutical Development and Technology.

Websites
Materials
It involves the selection of process/product/equipment/methods/materials for Failure Mode and Effect Analysisfor solid oral dosage forms.
Method
The method Failure Mode and Effect Analysis (FMEA) is used for the present study based on the advantages and appropriateness over other methods for solid oral dosage forms.
7.4

7.5

7.6

8. / Method of collection of data (including sampling procedures if any)
The data will be collected from the block diagram of the product/process which needs to be analysed to show the logical relationships between the components of the product/process steps/stages.
Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
-Does Not Require-
Has ethical clearance been obtained from your institution in case of 7.5?
-No-
[
List of References

1. Lawrence XY, AndreR, RobertL, RadhikaR, Lai ML, FrankH et al. US FDA question based review for generic drugs A new pharmaceutical quality assessment system. JGen Med 2007;4:239-48.
2. Short SM, Cogdill RP, Amico FD, Drennen JK, Anderson CA. A new definition of pharmaceutical quality Assembly of a risk simulation platform to investigate the impact of manufacturing/product variability on clinical performance. J Pharm Sci2010;99(12):5046-59.
3. Wakankar AA, Wang YJ, Eleanor CD, Stacey M, Dieter S, Josh G et al. On developing a process for conducting extractable–leachable assessment of components used for storage of biopharmaceuticals. J Pharm Sci 2010;(5): 2209-18.
4. Feng Q, Jun H, Hussain MA. Drug–polymer solubility and miscibility Stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci 2010;99(7):2941-47.
5. Yoshiteru K, Daisuke S,Tsuyoshi M, Akifumi N, Katsuhide T. Evaluation of risk and benefit in the application of near-infrared spectroscopy to monitor the granule coating process. Pharm Dev Technol;13:205-11.
6. Mortko CJ, Sheth AR, Narayan V, Li L, Farrer BT. Risk assessment and physicochemical characterization of a metastable dihydrate API phase for intravenous formulation development. J Pharm Sci 2010;99(12):4973-81.
7. Difeo TJ. Drug Product Development A technical review of chemistrymanufacturing and controls information for the support of pharmaceutical compound licensing activities. Drug Dev Ind Pharm 2003;29(9):939-58.
8. Dickinson PA, Wang WL, Stott PW, Townsend AI, Smart JP, Parviz G et al. Clinical relevance of dissolution testing in quality by design. AAPS J 2008;10(2):380-90.

1. Chien YH, Sherry KM. Prediction of drug particle size and content uniformity in low dose solid dosage forms. Int J Pharm 2010;383(1-2):70-80.
2. Andreou JG, Stewart PJ, Morton DAV. Short term changes in drug agglomeration within interactive mixtures following blending. Int J Pharm 2009;372(1-2):1-11.

9. / Signature of the Candidate / (D.DEEPIKA)
10. / Remarks of the Guide / The topic selected for dissertation is satisfactory. Adequate equipment & chemicals are available to carry out the project work.
11 / Name and Designation
11.1 / Guide: / Mr. BALA MURUGAN K.S
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
BANGALORE-64.
11.2 / Signature of Guide / (BALA MURUGAN K.S)
11.3 / Co-Guide / V.FREDERIC
CIPLA INDUSTRIES INDIA PVT.LTD
VIRGO NAGAR,BANGALORE.
11.4 / Signature of Co- Guide / (V.FREDERIC)
11.5 / Head of the Department: / Dr.K. RAMESH.
PRINCIPAL & HEAD OF THE DEPARTMENT
DEPT. OF PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
BANGALORE-64.
11.6 / Signature of HOD / (Dr.K. RAMESH)
12.1 / Remarks of the principal / All the required facilities will be provided to carry out dissertation work under the supervision of the guide and co-guide.
12.2 / Principal / Dr.K. RAMESH.
PRINCIPAL
KARNATAKA COLLEGE OF PHARMACY
BANGALORE-64.
12.3 / Signature of the Principal / (Dr. K. RAMESH)