European Guidance On:
HOW TO CARRY OUT A RISK ASSESSMENT

At EU-level there are not fixed rules about how risk assessments should be undertaken (you should check the specific legislation relating to risk assessment in your country). However, there are two principles which should always be borne in mind when approaching a risk assessment:

to structure the assessment to ensure that all relevant hazards and risks are addressed (e.g. not to overlook tasks, such as cleaning, that might take place out of normal working hours, or ancillary departments such as waste compacting);

when a risk is identified, to begin assessment from first principles by asking whether the risk can be eliminated.

A stepwise approach to risk assessment

The European Guidance on risk assessment at work proposes an approach based on a number of different steps. This is not the only method of carrying out a risk assessment, there are a variety of methodologies for achieving the same objective. There is no single “right” way to do a risk assessment and different approaches can work in different circumstances.

For most businesses, especially small and medium-sized enterprises, a straightforward five-step approach (incorporating elements of risk management) such as the one presented below should work well.

Step 1. Identifying hazards and those at risk

Looking for those things at work that have the potential to cause harm, and identifying workers who may be exposed to the hazards.

Step 2. Evaluating and prioritising risks

Estimating the existing risks (the severity and probability of possible harm…) and prioritising them in order of importance.

Step 3. Deciding on preventive action

Identifying the appropriate measures to eliminate or control the risks.

Step 4. Taking action

Putting in place the preventive and protective measures through a prioritisation plan.

Step 5. Monitoring and reviewing

The assessment should be reviewed at regular intervals to ensure that it remains up to date.

However, it is important to know that there are other methods that work equally well, particularly for more complex risks and circumstances. Which approach to assessment is applied will depend upon:

the nature of the workplace (e.g. a fixed establishment, or a transitory one);

the type of process (e.g. repeated operations, developing/changing processes, work on demand);

the task performed (e.g. repetitive, occasional or high risk);

technical complexity.

In some cases a single exercise covering all risks in a workplace or activity may be appropriate. In other cases, different approaches may be appropriate to different parts of a workplace.

Documenting the risk assessment

A record of the results of risk assessments at work should be kept. Such a record can be used as a basis for:

information to be passed to the persons concerned;

monitoring to assess whether necessary measures have been introduced;

evidence to be produced for supervisory authorities;

any revision if circumstances change.

A record of at least the following details is recommended:

name and function of the person(s) carrying out the examination;

the hazards and risks that were identified;

the groups of workers who face particular risks;

the necessary protection measures;

details of the introduction of the measures, such as the name of the person responsible and date;

details of subsequent monitoring and reviewing arrangements, including dates and the people involved;

details of the involvement of workers and their representatives in the risk assessment process.

The records of assessments should be drawn up with the consultation and participation of workers and/or their representatives and made available to them for information. The workers concerned should, in any case, be informed of the outcome of each assessment that relates to their work station, and the action to be taken as a result of the assessment.

What is Clinical Trail?

What is a Clinical Trial?

Clinical trials are research programs involving people who volunteer to test a new ‘treatment’. Clinical trials aim to find out whether medical, surgical or behavioral interventions work, and if they are safe and effective in management or prevention of disease.The word intervention is a common term used for new or improved treatments, management programs, new detection or prevention methods.To determine if the intervention treatment is effective, clinical trials compare two or more groups that receive different treatments.

The ICH document “General Considerations for Clinical Trials” is intended to:
a) describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products.
b) facilitate the evaluation and acceptance of foreign clinical trial data by promoting a common understanding of general principles, general approaches and the definition of relevant terms.
c) present an overview of the ICH clinical safety and efficacy documents and
facilitate the user’s access to guidance pertinent to clinical trials within these
documents. The relevant ICH documents are listed in Annex 1.
d) provide a separate glossary of terms used in the ICH clinical safety and efficacy
related documents that pertain to clinical trials and indicate which documents
contain them.
For the sake of brevity, the term “drug” has been used in this document. It should be
considered synonymous with “investigational (medicinal) product”, “medicinal
product” and “pharmaceutical” including vaccines and other biological products. The
principles established in this guideline may also be applied to other clinical
investigations (e.g. radiotherapy, psychotherapy, surgery, medical devices and
alternative therapies)

Type of Study The objective of the Study Study Examples
Human Pharmacology • Assess tolerance

• Define/describe PK[1]and PD[2]

• Explore drug metabolism and drug interactions

• Estimate activity

• Dose-tolerance studies

• Single and multiple dose PK and/or PD studies

• Drug interaction studies

Therapeutic

Exploratory

• Explore use for the targeted indication

• Estimate dosage for subsequent studies

• Provide a basis for confirmatory study design, endpoints, methodologies

• Earliest trials of relatively short duration in well- defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures

• Dose-response exploration studies

Therapeutic

Confirmatory

• Demonstrate/confirm

efficacy

• Establish safety profile

• Provide an adequate basis for assessing the benefit/risk relationship to support licensing

• Establish a dose-response relationship

• Adequate, and well-controlled studies to establish the efficacy

• Randomized parallel dose-response studies

• Clinical safety studies

• Studies of mortality/ morbidity outcomes

• Large simple trials

• Comparative studies

Therapeutic Use • Refine understanding of benefit/risk relationship in general or special populations and/or environments

• Identify less common adverse reactions

• Refine dosing recommendation

• Comparative effectiveness studies

• Studies of mortality/morbidity outcomes

• Studies of additional endpoints

• Large simple trials

• Pharmacoeconomic studies

[1] Pharmacokinetics[2] Pharmacodynamics

Phase I (Most typical kind of study: Human Pharmacology)

Phase I starts with the initial administration of an investigational new drug into humans.Although human pharmacology studies are typically identified with Phase I, they may also be indicated at other points in the development sequence. Studies in this phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer subjects or certain types of patients, e.g. patients with mild hypertension. Drugs with significant potential toxicity, e.g. cytotoxic drugs, are usually studied in patients. Studies in this phase can be open, baseline controlled or may use randomization and blinding, to improve the validity of observations.Studies conducted in Phase I typically involve one or a combination of the following aspects:

a) Estimation of Initial Safety and Tolerability

The initial and subsequent administration of an investigational new drug into humans is usually intended to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies typically include both single and multiple dose administration.

b) Pharmacokinetics

Characterization of a drug’s absorption, distribution, metabolism, and excretion continues throughout the development plan. Their preliminary characterization is an important goal of Phase I. Pharmacokinetics may be assessed via separate studies or as a part of efficacy, safety and tolerance studies. Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. For many orally administered drugs, especially modified release products, the study of food effects on bioavailability is important. Obtaining pharmacokinetic information in sub-populations such as patients with impaired elimination (renal or hepatic failure), the elderly, children, women and ethnic subgroups should be considered. Drug-drug interaction studies are important for many drugs; these are generally performed in phases beyond Phase I but studies in animals and in vitro studies of metabolism and potential interactions may lead to doing such studies earlier.

c) Assessment of Pharmacodynamics

Depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease. In patients, if there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies.

d) Early Measurement of Drug Activity

Preliminary studies of the activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later phases but may be appropriate when the drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.

Phase II (Most typical kind of study: Therapeutic Exploratory)

Phase II is usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients.Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparisons with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population and are closely monitored.An important goal for this phase is to determine the dose(s) and regimen for Phase III trials. Early studies in this phase often utilize dose escalation designs (see ICH E4) to give an early estimate of dose-response and later studies may confirm the dose-response relationship for the indication in question by using recognized parallel dose-response designs (could also be deferred to phase III). Confirmatory dose response studies may be conducted in Phase II or left for Phase III. Doses used in Phase II are usually but not always less than the highest doses used in Phase I.Additional objectives of clinical trials conducted in Phase II may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further study in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.

Phase III (Most typical kind of study: Therapeutic Confirmatory)

Phase III usually is considered, to begin with, the initiation of studies in which the primary objective is to demonstrate or confirm therapeutic benefit.Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies are intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationship, or explore the drug’s use in wider populations, in different stages of the disease, or in combination with another drug. For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be started in Phase II (see ICH E1). ICH E1 and ICH E7 describe the overall clinical safety database considerations for chronically administered drugs and drugs used in the elderly. These studies carried out in Phase III complete the information needed to support adequate instructions for use of the drug (official product information).

Phase IV (Variety of Studies: – Therapeutic Use)

Phase IV begins after drug approval. Therapeutic use studies go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug’s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies and studies designed to support use under the approved indication, e.g. mortality/morbidity studies, epidemiological studies.

Development of an application unrelated to the originally approved use

After initial approval, drug development may continue with studies of new or modified indications, new dosage regimens, new routes of administration or additional patient populations. If a new dose, formulation or combination is studied, additional human pharmacology studies may be indicated, necessitating a new development plan.The need for some studies may be obviated by the availability of data from the original development plan or from therapeutic use.

Reference:- GENERAL CONSIDERATIONS FOR CLINICAL TRIALS E8

Pharmaceutical Quality System Elements & Change Management System (ICHQ10)

Pharmaceutical Quality System Elements & Change Management System As per ICH Q10

The elements described below might be, required in part under regional GMP
regulations. However, the Q10 model’s intent is to enhance these elements in order to
promote the lifecycle approach to product quality. These four elements are:
• Process performance and product quality monitoring system;
• Corrective action and preventive action (CAPA) system;
• Change management system;                                                                                                        • Management review of process performance and product quality.
These elements should be applied in a manner that is appropriate and proportionate
to each of the product lifecycle stages, recognising the differences among, and the
different goals of, each stage. Throughout the product lifecycle, companies are
encouraged to evaluate opportunities for innovative approaches to improve product
quality. Each element is followed by a table of example applications of the element to the
stages of the pharmaceutical lifecycle.

Process Performance and Product Quality Monitoring System

Pharmaceutical companies should plan and execute a system for the monitoring of
process performance and product quality to ensure a state of control is maintained. An
effective monitoring system provides assurance of the continued capability of
processes and controls to produce a product of desired quality and to identify areas for
continual improvement. The process performance and product quality monitoring
system should:
(a) Use quality risk management to establish the control strategy. This can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, inprocess controls, finished product specifications, and the associated methods and frequency of monitoring and control. The control strategy should facilitate timely feedback / feed forward and appropriate corrective action and preventive action;
(b) Provide the tools for measurement and analysis of parameters and attributes identified in the control strategy (e.g., data management and statistical tools);
(c) Analyse parameters and attributes identified in the control strategy to verify continued operation within a state of control;
(d) Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation;
(e) Include feedback on product quality from both internal and external sources,
e.g., complaints, product rejections, non-conformances, recalls, deviations,
audits and regulatory inspections and findings;
(f) Provide knowledge to enhance process understanding, enrich the design space
(where established), and enable innovative approaches to process validation

Table I: Application of Process Performance and Product Quality Monitoring System throughout the Product Lifecycle

Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation
Process and product knowledge generated and process and product monitoring conducted throughout development can be used to establish a control strategy for manufacturing Monitoring during scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained during transfer and scale up activities can be useful in further developing the control strategy. A well-defined system for process performance and product quality monitoring should be applied to assure performance within a state of control and to identify improvement areas. Once manufacturing ceases, monitoring such as stability testing should continue to completion of the studies. Appropriate action on marketed product should continue to be executed according to regional regulations.

Corrective Action and Preventive Action (CAPA) System

The pharmaceutical company should have a system for implementing corrective
actions and preventive actions resulting from the investigation of complaints, product
rejections, non-conformances, recalls, deviations, audits, regulatory inspections and
findings, and trends from process performance and product quality monitoring. A
structured approach to the investigation process should be used with the objective of
determining the root cause. The level of effort, formality, and documentation of the
investigation should be commensurate with the level of risk, in line with ICH Q9.
CAPA methodology should result in product and process improvements and enhanced
product and process understanding.

Table II: Application of Corrective Action and Preventive Action System throughout the Product Lifecycle

Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation
Product or process variability is explored. CAPA methodology is useful where corrective actions and preventive actions are incorporated into the iterative design and development process. CAPA can be used as an effective system for feedback, feedforward and continual improvement. CAPA should be used and the effectiveness of the actions should be evaluated CAPA should continue after the product is discontinued. The impact on product remaining on the market should be considered as well as other products which might be impacted.

Change Management System

Innovation, continual improvement, the outputs of process performance and product
quality monitoring and CAPA drive change. In order to evaluate, approve and implement these changes properly, a company should have an effective change management system. There is generally a difference in formality of change management processes prior to the initial regulatory submission and after submission, where changes to the regulatory filing might be required under regional requirements.
The change management system ensures continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance there are no
unintended consequences of the change.
The change management system should include the following, as appropriate for the
stage of the lifecycle:

(a) Quality risk management should be utilised to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk;
(b) Proposed changes should be evaluated relative to the marketing authorisation, including design space, where established, and/or current product and process understanding. There should be an assessment to determine whether a change to the regulatory filing is required under regional requirements. As stated in ICH Q8, working within the design space is not considered a change (from a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all changes should be evaluated by a company’s change management system;
(c) Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set;
(d) After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on product quality.

Table III: Application of Change Management System throughout the Product Lifecycle.

Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation
Change is an inherent part of the development process and should be documented; the formality of the change management process should be consistent with the stage of pharmaceutical development. The change management system should provide management and documentation of adjustments made to the process during technology transfer activities. A formal change management system should be in place for commercial manufacturing. Oversight by the quality unit should provide assurance of appropriate science and risk based assessments. Any changes after product discontinuation should go through an appropriate change management system.

Management Review of Process Performance and Product Quality

Management review should provide assurance that process performance and product
quality are managed over the lifecycle. Depending on the size and complexity of the
company, management review can be a series of reviews at various levels of
management and should include a timely and effective communication and escalation
process to raise appropriate quality issues to senior levels of management for review.
(a) The management review system should include:
(1) The results of regulatory inspections and findings, audits and other
assessments, and commitments made to regulatory authorities;
(2) Periodic quality reviews, that can include:
(i) Measures of customer satisfaction such as product quality
complaints and recalls;
(ii) Conclusions of process performance and product quality
monitoring;
(iii)The effectiveness of process and product changes including those
arising from corrective action and preventive actions.
(3) Any follow-up actions from previous management reviews.
(b) The management review system should identify appropriate actions, such as:
(1) Improvements to manufacturing processes and products;
(2) Provision, training and/or realignment of resources;
(3) Capture and dissemination of knowledge.

Table IV: Application of Management Review of Process Performance and Product Quality throughout the Product Lifecycle.

Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation
Aspects of management review can be performed to ensure adequacy of the product and process design. Aspects of management review should be performed to ensure the developed product and process can be manufactured at commercial scale. Management review should be a structured system, as described above, and should support continual improvement Management review should include such items as product stability and product quality complaints.