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21 Cover Story 10 I hereby present yet another issue of Microbioz India. It is a “Pharma Special Issue” which is supported by the cover story titled “Risk assessment and pharmaceutical processing hazards” authored by Dr. Tim Sandle.

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ear friends and readers, with a great sense of excitement, I inform you that your favourite magazine Microbioz India has completed three years of beautiful journey which became possible all because of your extreme love, support and encouragement all through these years. So, with gratitude in heart for all the support and your presence, I hereby present yet another issue of Microbioz India. It is a “Pharma Special Issue” which is supported by the cover story titled “Risk assessment and pharmaceutical processing hazards” authored by Dr. Tim Sandle, Ph.D, Scientist, Bioproduct Laboartory, U.K. The article focusses on some of the main hazards to pharmaceutical manufacturing and provides a basis for assessing risks.

Because, even though the pharmaceutical medicines are considered to be efficacious and safe for consumption as they are licenced and directed by practitioner, still there is always a chance of expected manufacturing problems. So, assessing risk for hazards during pharmaceutical processing helps to create a product of suitable quality and ultimately provides an invaluable step for protecting the patient or consumer of the medicine.

The magazine also includes a List of Upcoming Events and Conferences which are going to be organized around the world recently along with the latest research news from topmost universities to widen your knowledge about what is going on in the field of research around the world. The research news are collected from number of areas like Biotechnology, Microbiology and Health Sciences to keep you updated with latest breakthroughs and discoveries around the globe. The magazine also contains Open Scholarship Positions from topmost universities of the world which our young readers can grab to pursue higher studies.

The magazine is incomplete without the love and support of the valuable readers. Your valuable feedback and suggestions are always welcome as they help us come with better content each time. For any further value addition, kindly write to us at editor@microbiozindia.com.

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harmaceutical medicines are expected to be efficacious and to perform according to the product licence or as directed by the medical practitioner.

Medicines are also expected to be safe, and the basis of a safe medicine is one that has been manufactured consistently and with a review of potential manufacturing hazards completed.

Although manufacturing problems can occur unexpectedly, the impact of incidences that could lead to contamination can be managed better should the risks be identified in advance and some form of proactive risk assessment conducted.

This article considers some of the main hazards to pharmaceutical manufacturing and provides a basis for assessing risks. This type of approach helps to create a product of suitable quality and ultimately provides an invaluable step for protecting the patient or consumer of the medicine.

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The basics of risk assessment Hazards, of varying types, are an ever present feature of pharmaceuticals and healthcare. Hazards can have serious consequences, both in relation to unsuitable products or in terms of presenting risks to patients. Often the term risk, as the outcome of an assessment, is confused with the word hazard. In fact, risk is the expression of a hazard. A hazard is the potential source of harm, and one that either exists or does not exist (it is the assessment of risk that quantified or qualifies a hazard) (Bahr, 1997).

Some hazards are capable of causing more harm than others (different degrees of severity).

Risk is consequence of a hazard occurring. It is clearer to consider risk as a probabilistic concept and it is inseparable from the factors of probability and uncertainty. Thus it follows that risk is the probability of harm.

Thus the impact of hazards can be assessed through risk assessment, which evaluates the consequence of each hazard in terms of its severity and the likelihood that an event will occur.

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Cover Story Once identified, such risk outcomes can be assessed to see if they can be mitigated and where not (or not to an acceptably low level), detection methods can be put in place. These elements form the ‘risk assessment’ process. In essence risk assessment involves assessing probabilities and managing

The U.S. Food and Drug Administration (FDA), in particular, places a significant emphasis upon pharmaceutical manufacturers conducting risk assessment. uncertainty (Antunes and Gonzalez, 2015).

Risk assessment can be expressed as a formal process, and here such an activity based on a series of key steps. In short, these involve:  Establishing the context and environment that could present a risk.  Identifying the hazards and considering the risks these hazards present.  Analyzing the risks, including an assessment of the various contributing factors.  Evaluating and prioritizing the risks in terms of further actions required.  Identifying the range of options available to tackle the risks and deciding how to implement risk mitigation strategies.

The outcome (consequences) of risk assessment can be expressed numerically (how severe something could be) and their likelihoods of occurrence are expressed as probabilities or frequencies (how often something could happen). The total risk is the expected threat: the relationship between the severity and the probabilities. This is normally expressed by multiplication: Risk

=

The FDA approach is outlined in the document "Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach", a document that was issued in draft form in 2002 (with a final version in 2003). The FDA document was very important for promoting risk management (in a sense it laid down a marker for the industry), and it presented the first structured approach to the topic, supported by some risk assessment tools that could be applied (Haleem et al, 2015). The use of more systematic tools represented the shift away from tick box approaches to more scientific assessments of risk.

This regulatory perspective takes the form of quality risk management (or QRM). QRM a systematic process of organizing information to support a risk decision to be made within a risk management process; it also makes a key contribution to the final decision making process (O'Donnell et al, 2012). QRM consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Key to the QRM process is:  risk assessment,  risk control,  risk communication (including incorporating risk awareness into the organizational culture),  risk review, In the context of the quality of the drug (medicinal) product across the product lifecycle.

Severity score x Probability score

Expectations of regulatory agencies Risk management and risk concepts are embedded in current Good Manufacturing Practices (GMP) (Patel and Chotai, 2008), and outlines of approaches that can be used for conducting risk assessment, along with methodologies, are described in regulatory guidance documents. The U.S. Food and Drug Administration (FDA), in particular, places a significant emphasis upon pharmaceutical manufacturers conducting risk assessment.

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Hazards in pharmaceutical processing Safeguarding the pharmaceutical manufacturing process from risk is achieved through the identification of hazards. Hazards can be categorized into different types. Examples of hazard classification are:

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Cover Story  Physical hazards. These are factors that can cause physical harm to a person or damage to equipment.  Chemical hazards are substances that can cause harm to a person or product.  Biological hazards are biological agents that can cause harm to the human body or adulterate a product. This includes microorganisms and microbial toxins.  Psychological hazards. These would include psychological factors or personnel fatigue.  Ergonomic hazards. This would include factors such as access to equipment.

With pharmaceuticals and healthcare, when performing hazard analysis potential risks in relation to the following should be considered:           

materials and ingredients; physical characteristics and composition of the product; processing procedures; microorganisms; premises; equipment; packaging; sanitation and hygiene; personnel – human error; utilities; supply chain

Examining for hazards can extend across all facilities and types of manufacturing. The remainder of this article looks at some examples of hazards.

Microbial contamination Microbial contamination can occur at each stage of the pharmaceutical manufacturing process, from in-coming raw materials, through product formulation, to packaging; and additionally, for sterile products, with terminal sterilization or aseptic filling.

The contamination risk may relate to concern with the numbers of microorganism or with specific pathogens (or 'objectionable microorganisms’). The relative risk from such contamination will relate to the numbers of organisms; the possible routes that contamination transfer could take; the particular stage of the process; the systems in place to remove or reduce microbial levels; and the protective measures in place.

Personnel People are a major contributor (and often unpredictable) of microbial contamination. Some more explicit reasons for this include people continuously shedding particles into their surroundings, many of which will be carrying microorganisms on them. Cleanroom garments do not contain all of the organisms present on human skin.

Special focus can be on the risk assessment and risk control of, for example.  product quality risks;  adverse impact to patient health based on product quality defects;  product supply interruption to patients;  GMP and regulatory compliance risks;  multisite risks;  multiproduct risks;  ageing facility risks  new facility and changes to existing facility, e.g. startups, new commercial  manufacturing processes, technology transfers and product discontinuation Microbioz India, March 2017

Risk based systems of control should be in place for dealing with people. These should extend to garments and behaviors, and areas where personnel can have access. For instance, correct gowning is critical for a significant microbial risk can be presented to the operating environment.

Hazard identification and control are of great concern to pharmaceutical manufacturers and regulators.

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Pharmaceutical formulation Errors can occur with pharmaceutical processing, presenting different risks. Pharmaceutical formulation describes the process by which different chemical substances, including the active drug, are combined to produce a final medicinal product (Simler et al, 2008).

Processing problems can arise at different stages of the process. These include:  Ensuring that the drug product is both stable and acceptable to the patient.  Designing appropriate pre-formulation studies to characterize a drug's physical, chemical, and mechanical properties. This is necessary so that appropriate ingredients (excipients) can be selected.  Running formulation studies to assess factors that can influence the bioavailability of the active ingredient and thus activity of the medicinal product. This can include an assessment of particle size, polymorphism, pH, and solubility.  Uniformity during manufacture. Here the dosage should have a uniform appearance. This can be complicated if various dosage forms exist for a single particular drug.

This can occur when different medical conditions can warrant different routes of administration.  Patient safety. This ranges from taste, tablet hardness, or capsule disintegration, in relation to non-sterile medications (plus an absence of pathogenic organisms) to the avoidance of microbial contamination in sterile drug products.  With tablet preparation, ensuring that each tablet contains a variety of other potentially inert substances apart from the drug itself. It is important that the encapsulated drug is compatible with these other substances in a way that does not cause harm, whether direct or indirect.

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 With parenteral products (injectable formulations used for intravenous, subcutaneous, intramuscular, and intraarticular administration) these are commonly required to be sterile (that is free from viable microorganisms, microbial by-products and visible particulates).

Although sterility is paramount, there are other hazards.

For instance, most parenteral formulations are unstable at higher temperatures and require storage at refrigerated or sometimes frozen conditions. Moreover, most protein formulations are parenteral due to the fragile nature of the molecule which would be destroyed by enteric administration.  Stability studies to assess the behavior of the drug product over time.  This involves subjecting the final product to a variety of stress conditions including freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation and therefore its mitigation. In addition, stability studies are carried out to test whether temperature, humidity, oxidation, or photolysis (ultraviolet light or visible light) have any effect.  A key risk with processing is with chemical mix-ups.

There are steps that can be taken to avoid mix-ups happening, for example weighing out all amounts of a chemical for all batches consecutively, rather than weighing out all of the chemicals for each batch individually.

Drug distribution The safe distribution of medicines is of importance. The logistics process of delivering these drugs to the patient (cold chain) requires careful planning.

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Cover Story Breakdowns with the cold chain can interfere with delivery of drugs, especially temperature fluctuations.

With these considerations, risk assessment is a powerful tool for understanding and addressing pharmaceutical industry hazards.

Summary

References

Hazard identification and control are of great concern to pharmaceutical manufacturers and regulators. In recent years there has been a regulatory drive towards the use of formal and scientifically sound risk assessment tools as part of hazard control. This article has highlighted that, in undertaking risk assessments, it is important to attempt risk mitigation and to attempt to lower the risk until the risk can be lowered no further. This involves identifying actions to reduce the probability of event and to reduce the severity of event. When this can be taken no further the focus should move towards providing a more reliable detection method designed to initiate a reliable response to a risk event.

Once risk assessments have been completed it is important that risk assessments should be periodically re-assessed so that process and technological changes are captured and reviewed.

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Antunes, R. and Gonzalez, V. (2015) A Production Model for Construction: A Theoretical Framework. Buildings 5 (1): 209–228

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Bahr, N. J. (1997). System Safety Engineering and Risk Assessment: A Practical Approach (Chemical Engineering) (1st ed.). London: Taylor & Francis Group, pp2-5

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FDA (2003). Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach, 2003. Food and Drug Administration, Rockville: MD.

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Haleem, R. M., Salem, M. Y., Fatahallah, F. A. and Abderfattah, L. E. (2015) Quality in the pharmaceutical industry - a literature review, Saudi Pharm. J., 23 (5): 463-469

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Patel, K. T. and Chotai, N. P. (2008) Pharmaceutical GMP: past, present and future - a review, Pharmazie, 63 (4): 241-255.

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Simler, R., Walsh, G., Mattaliano, R.J., Guziewicz, N., and Perez-Ramirez, B. (2008). Maximizing Data Collection and Analysis During Preformulation of Biotherapeutic Proteins. BioProcess International 6(10), 38-45

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