Risk Assessment

Risk assessment is essential to identify the unit operations of drug product manufacturing process with the potential to impact on product CQAs. The ICH Q8(R2) recommends the use of risk assessment tools during product development in order to select

Attribute	Target product profile	Rationale
Dosage form	Polymeric nanoparticle, carbon- based vehicle, polymeric micelles, liposomes, solid lipid nanoparticles, niosomes, transferosomes, nanogel, nanoemulsion	The nanocarriers were identified as potential drug delivery systems for the brain, due to the different strategies to surpass the BBB [2, 3].
Dosage form design	Injectables: lyophilised, concentrate for dilution Nasal sprays: liquid, powder and semisolid	Some products may require lyophilisation to increase the stability of the finished product [16]. However, it is desirable to avoid this complex process which increases the development time and cost of the drug product.
Route of administration	Intravenous, nasal	Intravenous administration is known to provide the highest drug bioavailability. However, it is invasive and the manufacturing process is costly. Other routes of administration should be explored. For example, the nasal route could provide a fast delivery from the nasal cavity to the brain, and it is less invasive [14,17,18].

Attribute		Target product profile	Rationale
Dosage strength		Product specific	The selected strength should guarantee the pharmacological effect. It depends on the drug, the route of administration and the ability of the formulation to deliver the drug to the site of action.
Pharmacokinetics		Product specific	The determination of the PK is essential to define the drug bioavailability, the safety and the toxicity of the medicinal product.
Stability		Long-term physicochemical stability Protection from light and freezing (when applicable) Shelf-life of at least 24 months	The quality of the product should be maintained during storage in order to define the product shelf-life and to ensure the commercial viability of the product. Some products may require special storage conditions to avoid degradation and maintain the quality ofthe product [19].
Drug product quality attributes	Appearance	According to the dosage form and intended application site, there are acceptance limits defined in the pharmacopoeias and in the regulatory authorities’ guidance documents (e.g. FDA, EMA, ICH). Detailed target limits are depicted in the CQAs (Table 11.2).	The appearance of the drug product depends on the raw materials' characteristics as well as on the dosage form design. Nevertheless, the colour, clarity (liquid dosage forms) and cake appearance (lyophilised products) should be defined [20].

Attribute		Target product profile	Rationale
	Mean particle size		The nanocarriers’ small dimensions are comparable to endogenous molecules and, therefore, offer the potential to overcome the BBB [21].
	Particle size distribution		High variability in the nanocarriers' size is not desirable because of the possibility of having different drug release behaviour and intra- and intersubject drug biodistribution [13, 22].
	Morphology		The nanocarriers’ morphology may influence the drug loading, retention and release [23]. For each nanocarrier the best morphology should be defined.
	Surface charge		A balance should be established between neutral, positive and negative surface charge: a neutral surface charge allows the nanocarriers to escape the reticuloendothelial system; a positive surface charge facilitates the interaction with the lipid membranes which are negatively charged; a negative surface promotes the colloidal stability of the drug product [13, 24, 25].

Attribute		Target product profile	Rationale
	DS and raw materials Identification		From a quality standpoint, it is crucial to ensure the correct identification of the selected materials [26, 27].
	DS polymorphism		In the majority of nanocarriers, the drug substance is solubilised before the encapsulation. In these cases, the polymorphism does not represent an issue in terms of drug bioavailability but may influence the formulation composition [e.g. solvent selection) as well as the manufacturing process [e.g. solubilisation time and/or order of addition).
	Uniformity of dosage units		The uniformity in the amount of the drug substance is mandatory to ensure the consistency of the dosage administered to the patients.
	DS and functional excipients assay		The DS must be present in the amount stated in the label claim, which means present in the amount which provides the desired efficacy [28, 29]. In addition, the ratio between the raw materials could influence the product performance.

Attribute		Target product profile	Rationale
	Encapsulated and free drug substance (DS)		High encapsulation efficiency is indicative of an efficient and cost-effective process. Also, the high drug concentration can establish a suitable gradient for drug delivery [2].
	DS and functional excipients degradation products		There are limits for degradation products in order to guarantee the quality and stability of the drug product, as well as to limit the exposure to potentially toxic impurities [30].
	Residual solvents		The use of organic solvents is very common in the development and manufacturing of nanocarriers. There are recommendations regarding the admitted solvents and their limits [31].
	In vitro release of the DS		An in vitro drug release method, capable of providing a good IVIV correlation, is useful to demonstrate consistent quality and performance of the drug product [32]. Keep in mind that it may be possible to develop a method for quality control purposes only and a method with the ability to provide a better insight on the product performance in vivo.

Attribute		Target product profile	Rationale
	Osmolality		An isotonic product is desirable, both for the intravenous and nasal route, in order to avoid tissue irritation and cells damage.
	pH		pH values different from the pH of the intended administration site may cause irritation. Nevertheless, a balance should be established between the drug permeability, stability and patient safety.
	Viscosity		No special equipment or devices are required for manufacturing, storage and delivery when the product has a low viscosity.
	Moisture content		The moisture content is applicable for lyophilised products in order to ensure a suitable shelf-life.
	Microbial limits		Fornonsterile products, the microbiological quality should limit/preventthe occurrence of adverse reactions due to the presence of a high level of microorganisms. The microbiological quality must be maintained throughout the product shelf-life.

(Continued)

Attribute		Target product profile	Rationale
	Sterility		Injectable drug products are meant to enter directly to the blood circulation. Therefore, it is mandatory to have a product free from microorganisms, pyrogen content and bacterial endotoxins.
	Pyrogen test
	Bacterial endotoxins
Drug product composition		Biocompatible, biodegradable, nontoxic, compliant with GMP and other compendial requirements	All the raw materials used in the manufacturing of drug products should have certain properties which ensure its quality and safety. Also, for the US market it is desirable to choose raw materials present in the Inactive Ingredients Database, to avoid additional toxicological tests prior to the approval of the drug product.
Dilution/ reconstimtion buffer		To be determined	The product properties and performance must be maintained after dilution and/or reconstitution.
Dilution/ reconstitution process		To be determined	The process for dilution/reconstitution must guarantee the product properties and performance. The stability of the diluted product must be determined as well.

Attribute	Target product profile	Rationale
Container closure system	Injectables: clear type I glass vial with an elastomeric stopper	Needed to achieve the target shelf-life and to ensure the container integrity during shipment. In the case of sprays, the performance and usability should also be evaluated.
Container closure system	Nasal sprays: type 1 glass bottles or plastic bottles (e.g. polyethylene, polypropylene, PET)
Fill volume	A volume which enables the extraction of the labelled volume which is to be withdrawn.	The volume present must ensure correct dosing.

Quality attributes		Target	Is this a CQA?	Justification
Physical attributes	Appearance	Depends on formulation (to be determined)	Yes	The colour and clarity of the drug product may be quality- and stability-indicating, which can be linked to safety and efficacy. Therefore, they should be evaluated during development.
	Mean particle size	Below 200 nm	Yes	The particle size and particle size distribution will affect drug PK. Process variables may affect
	Particle size distribution	Narrow	Yes	the nanocarrier size. Thus, mean particle size and size distribution should be evaluated throughout product and process development.
	Morphology/ lamellarity	Depends on formulation (to be determined)	Yes	Nanocarrier morphology and lamellarity (in the case of liposomes) influence drug loading, drug retention, and the rate of drug release. These CQAs may be affected by process variables. Therefore, morphology and lamellarity should be investigated throughout product and process development.
	Surface charge	-30 mV to 30 mV	Yes	Surface charge on nanocarriers can affect the clearance, tissue distribution and cellular uptake. The surface charge may be influenced by formulation and process parameters, so the zeta potential will be investigated throughout formulation and process development.

Quality attributes	Target	Is this a CQA?	Justification
Identification	Positive for the materials in use	Yes	Identification is critical for safety and efficacy. However, it can be effectively controlled by the quality management system and should be monitored at drug product quality control release.
Assay DS	USP: 90%-110% of label claim EP: 95%-105% of label claim	Yes	Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay should be evaluated throughout product and process development.
Assay of functional excipients	Molar ratio drug substance:total lipids Molar ratio drug substance:polymer Molar ratio lipid:lipid	Yes	The molar ratio between the formulation components demonstrates consistency with the intended formulation and influence the drug loading. Changes in the molar ratio can influence the bioavailability and efficacy of the product. Process variables may affect the assay of the drug product, so this CQA should be evaluated throughout product and process development.
Uniformity of dosage units	Conforms to USP <905>	Yes	The consistency of dosage units is linked to the safety and efficacy of the drug products. Formulation, process parameters and container closure influence this CQA.

Quality attributes	Target	Is this a CQA?	justification
Fill volume	Injectables: Fill volume per vial according to the compendial recommendation (USP <697>) Nasal sprays: Minimum fill according to the compendial recommendation (USP <755>)	Yes	Inadequate volume in the container may lead to insufficient dosing. Process parameters and the container closure affect this CQA. Fill volume per vial should be investigated during product and process development.
DS and functional excipients degradation products	MeetICH Q3B(R2) requirements	Yes	Degradation products can impact safety and must be controlled based on compendial/ ICH requirements to limit patient exposure. Formulation and process variables can impact degradation products. Therefore, degradation products should be assessed during product and process development.
In vitro drug release	Depends on formulation (to be determined)	Yes	Failure to meet the in vitro drug release specification can impact safety and efficacy. Both physical and chemical formulation stability as well as process variables affect the in vitro drug release. This CQA should be investigated throughout formulation and process development.

Quality attributes	Target	Is this a CQA?	justification
Leakage	As low as possible	Yes	Leakage during storage could have an impact on drug PK. Formulation and manufacturing variables may affect this CQA. This CQA should be investigated throughout formulation and process development.
Percentage of encapsulated DS	As high as possible	Yes	Free DS content could have an impact on drug PK. Formulation and manufacturing parameters may affect this CQA.
State of encapsulated DS	To be determined	Yes	The salt form/precipitated form of the DS could influence its release from the nanocarrier and, consequently, the PK. This CQA should be evaluated during process and formulation development.
Osmolality	Conforms to USP <785>	Yes	The osmolality should be compatible with the application site and the formulation stability. Osmolality values different from plasma osmolality may cause tissue irritation and damage to blood cells. The integrity of the nanocarriers may also be influenced by osmolality which can cause leakage of the drug substance. The osmolality may be affected by process and formulation variables, so this CQA should be evaluated during product and process development.

Quality attributes	Target	Is this a CQA?	justification
pH	Close to the pH of the intended administration site	Yes	The pH is critical for drug permeability, stability and patient safety. Both formulation and process variables affect the pH. Thus, pH should be assessed during product and process development.
Viscosity	As low as possible	Yes	No special equipment or devices are required for manufacturing, storage and delivery when the product has a low viscosity. Formulation and process variables impact on viscosity. Thus, this CQA should be evaluated throughout the development.
Residual solvents	Meet ICH Q3C(R6) requirements	Yes	Residual solvents can impact patient safety. Considering that solvents may not be completely removed during manufacturing, they should be quantified during product and process development.
Leachables and extractables	Conforms to USP <1663> and <1664>	Yes	Nanocarrier formulations have the potential to present leachables and extractables from plastic and rubber components. This may influence patient safety, so these should be evaluated throughout product and process development.

Quality attributes	Target	Is this a CQA?	justification
Microbial limits	Conforms to USP <1111>	Yes	Noncompliance with microbial limits will impact patient safety. The sterility, pyrogen content and bacterial endotoxins may be influenced by process and formulation parameters. Therefore, these CQAs should be investigated during product and process development.
Sterility	Conforms to USP <71 >	Yes
Pyrogen test	Conforms to USP <151>	Yes
Bacterial endotoxins	Conforms to USP <85>	Yes
Particulate matter in injections	Conforms to USP <788> and USP <790>	Yes	The presence of particulate matter in intravenous injections represents a potentially life-threatening health hazard. Both formulation and process variables may influence this CQA, so it should be evaluated throughout product and process development.
Lipid bilayer phase transition temperature	Depends on formulation (to be determined)	Yes	Equivalence in lipid bilayer phase transitions will contribute to demonstrating equivalence in bilayer fluidity and uniformity (FDA, 2018a). This affects drug release from the nanocarrier and drug PK. Formulation and manufacturing parameters may impact phase transition temperature. Thus, phase transition temperature should be assessed during product and process development.

Quality attributes	Target	Is this a CQA?	Justification
Moisture content	Depends on formulation (to be determined)	Yes	The residual water present in the lyophilised products may lead to the formation of degradation products, which could compromise the patient's safety. The moisture content is determined by formulation and process parameters, and for that it should be evaluated during development.

Identification of environmental, man, equipment and raw materials with the potential to influence nanocarriers' CQAs based on the cause-and-effect diagram

Figure 11.2 Identification of environmental, man, equipment and raw materials with the potential to influence nanocarriers' CQAs based on the cause-and-effect diagram.

and prioritise which material attributes and PPs should be studied (the factors or variables) [9]. Cause-and-effect diagram/fishbone/ Ishikawa diagram, risk estimation matrix (REM) and the failure mode and effects analysis (FMEA) are widely used tools for this purpose [4, 9, 10,12]. The cause-and-effect diagram is a qualitative tool, where environmental, man, equipment, raw materials and process variables are categorised according to their a priori importance aiming to explain the CQAs variation. Common variables can be defined for all types of nanocarriers (Fig. 11.2) and other variables are only applicable to specific manufacturing process of nanocarriers where the potential critical unit operations are linked to the CQAs. In the case of liposomes (Fig. 11.3) the manufacturing process might include the following major process steps: formation ofmultilamellar vesicles (MLVs) through ethanol injection, extrusion for size reduction and manufacturing of small unilamellar vesicles, tangential flow filtration for buffer exchange, active drug loading and finally a new tangential flow filtration for the removal of unencapsulated drug. The manufacturing of solid lipid nanoparticles (Fig. 11.4) starts with the formation of a coarse dispersion by highspeed homogenisation of the organic and aqueous phase, during the ultrasonication a pre-emulsion is formed and the final emulsion is obtained by high-speed homogenisation, and in the last step occurs the recrystallisation of the lipid nanoparticles. For each of these unit operations it is possible do identify PPs which have the potential to influence the product CQAs and construct cause-and-effect diagrams, as depicted in Figs. 11.3 and 11.4.

The FMEA and REM are quantitative tools which can be used alone or in combination with the cause-and-effect diagram [10,12]. Design of experiment (DoE) studies for formulation/process understanding and design space definition are recommend during development. Because it is not feasible to study all possible formulation and process variables during product development using DoE, the REM is often used to prioritise which ones are more likely to be critical and should be investigated - CMA and CPP identification [33]. The

Cause-and-effect diagram representing the link between process parameters in the manufacturing of liposomes which can interfere with the CQAs

Figure 11.3 Cause-and-effect diagram representing the link between process parameters in the manufacturing of liposomes which can interfere with the CQAs.

Cause-and-effect diagram representing the link between process parameters in the manufacturing of solid lipid nanoparticles which can interfere with the CQAs

Figure 11.4 Cause-and-effect diagram representing the link between process parameters in the manufacturing of solid lipid nanoparticles which can interfere with the CQAs.

REM ranks the variables considering the potential critically in terms of risk (high, medium or low risk level}. REM considers the severity and the probability of occurrence of each variable but does not take into consideration the detection, which is present in the FMEA risk assessment tool. The goal of the DoE studies is to increase the knowledge about the product and the process; therefore, it is important to study as much variables as possible, including the ones which are easily detected. When the probability of detection is included in the risk assessment, as in the case of FMEA tool, it is possible to document the actions related to the risk of failure, and in this sense, it is used for prevention and control during development and throughout product life cycle management. A REM (Table 11.3) was constructed to highlight the relation between five CQAs of liposomes (particle size, particle size distribution, in vitro release, assay and degradation products) and the PPs of the manufacturing of liposomes previously identified in the cause-and-effect diagram depicted on Fig. 11.2. The parameters with a high risk of influencing the CQAs are shaded in red, the medium risk in yellow and the low risk in green. For example, in the MLVs formation the temperature, addition and mixing speed were considered as high-risk factors for the particle size and particle distribution. The lipids present in the liposomes composition have a phase transition temperature which should be reached in order to promote the alignment of the polar heads and the vesicles' formation [34,35]. Therefore, there is a high probability that changes in the temperature impact on the CQAs mentioned, and when it occurs, the severity is very high because different particle sizes results in changes in the PK of the product. When different addition speed and mixing speed are applied, different mechanical stress is generated which will impact on the particle size and particle size distribution [34, 35]. In these cases, the probability of occurrence is high and the severity very high.

Risk Assessment

Risk assessment

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Q42. Why is the risk assessment process so important?

Q43. What are the potential problems with risk assessment?

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