ISPE-Risk MaPP, ICH Quality guidelines, EU GMP, and EMA guidance recommends a risk-based decision making in the pharmaceutical manufacturing. When different medicinal products are produced in shared facilities, the potential for cross-contamination is a concern. Medicinal products provide a benefit to the intended patient or target animal; however as a cross contaminant, they provide no benefit to the patient or target animal and may even pose a risk. Hence, the presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations. To this end, health based limits through the derivation of a safe threshold value should be employed to identify the risks posed. The derivation of such a threshold value (e.g. permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data. PDE is a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. It is synonymous to ADE (Acceptable Daily Exposure). PDE is a reflection of toxic potential of the compound; higher the PDE lower is the toxic potential. PDE is derived by a toxicologist from a structured scientific evaluation of relevant data.
PDE is used to determine the acceptable amount of a previous drug that may be allowed in the next drug as carry over cross contaminant. This acceptable level is called MACO (Maximum Allowable Carryover). The MACO is then used for the calculation of the maximum safe surface residue or rinse concentration (the operational cleaning limit), which takes into account the shared equipment surface areas or volumes of the rinse of equipment between products A and B. MACO = PDEPrevious x MBSnext TDDnext Where, MACO (Maximum Allowable Carryover): Acceptable transferred amount from the previous product into your next product (mg). PDE- Permitted daily exposure. MBSnext- Minimum batch size for the next product(s) (where MACO can end up) (mg) TDDnext: Standard therapeutic daily dose for the next product (mg/day). As evident from the equation, larger the PDE value, higher will be MACO. This means more amount of a relatively safe drug may be allowed as a cross-contaminant while highly toxic compound can be allowed only a minute amount in the next product.
Yes, HBELs should be established for all products. HBELs for highly hazardous products are expected to be completed in full as per the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) or equivalent.
No, LD50 is not an adequate point of departure to determine an HBEL.
Health-Based Exposure Limits should be determined by a person who has adequate expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determination of health-based exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE).
Toxicology being an inter-disciplinary science, an understanding of the physiology, biochemistry, pathology, endocrinology, pharmacology, clinical pharmacology, genetics, etc., is a must in order to make an integrated assessment of findings of toxicology studies and to identify potential signals from the clinical studies. Masters or PhD degree in the area of toxicology, veterinary medicine, human medicine, pharmacology etc. represents a relevant qualification that teaches these subjects. The depth and breadth of toxicology subjects covered in these courses vary. Certification by professional bodies in the field of toxicology is an endorsement of a person’s relevance of qualification and experience in the field of toxicology. Some of these certifications are based on successful completion of a written examination (ex: Diplomate of American Board of Toxicology), while others may be based on relevance of qualification and demonstration of actual practice of toxicology, and adequacy of experience in the toxicology field (ex: European Registered Toxicologist). In summary, the most critical attribute that a person should process in order to be able to derive a PDE is combination of relevant educational qualification, understanding of basic science of toxicology, and adequate experience in the field of toxicological risk assessment.
The aim of determining a health-based exposure limit is to ensure human safety, and consequently it is considered that good quality human clinical data is highly relevant. Unintended pharmacodynamic effects in patients caused by contaminating active substances may constitute a hazard thus clinical pharmacological data should be considered when identifying the critical effect. Consideration should be given to what extent the active substance in question has been associated with critical adverse effects in the clinical setting. If the most critical effect identified to determine a health-based exposure limit is based on pharmacological and/or toxicological effects observed in humans rather than animals, the use of the PDE formula may be inappropriate and a substance-specific assessment of the clinical data may be used for this purpose.
How can the HBEL model be applied to early phase Investigational Medicinal Products (IMPs) where limited data is available?
Health based exposure limits should be established based on all available data and as such assessments associated with IMPs should be regularly reviewed for presence of new data. Toxicology experts should also make judgments about the future potential of the material to demonstrate critical effects where key toxicological testing has not been completed (e.g. this may be based on comparison to other similar molecules where available) and any additional adjustment factors that may be appropriate. This would allow manufacturers to assume worst case and make sound judgments on the level of organisational and technical control measures required.
Should the HBEL be re-assessed throughout the phases of development of Investigational Medicinal Products (IMPs)?
Health-Based Exposure Limits should be established based on all available data, and particularly as the knowledge base for IMPs is continually evolving the basis for establishing the HBEL, should be regularly reviewed taking account of any new relevant data.
Is it acceptable to simply segregate products of a common therapeutic classification in a dedicated area as a means of controlling risk of cross contamination?
Manufacturers cannot just segregate common products from other product types as a means of dealing with the risk to patient and animal safety. Although this may prevent contamination of other product classes it does not address the possibility for cross contamination within product classes. This should include implementation of appropriate organisational and technical control measures to prevent contamination between such products within product specific HBELs.
Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be used to justify cleaning limits (To recommend an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of threshold levels as referred to in the GMP guideline. These levels can be used as a risk identification tool and can also be used to justify carry over limits used in cleaning validation.), it is not intended to be used to set cleaning limits at the level of the calculated HBEL. For existing products, manufacturer’s historically used cleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into account, they provide sufficient assurance that excursions above the HBEL will be prevented. A similar process should be adopted when establishing cleaning alert levels for products introduced into a facility for the first-time. Results above the alert cleaning limit should trigger an investigation and, where appropriate, corrective action to bring the cleaning process performance within the alert cleaning limits. Repeated excursions above the alert cleaning limit will not be considered acceptable where these indicate that the cleaning method is not in control. Recognised appropriate statistical methods may be used to determine whether the cleaning process is in control or not.
Once the health based assessment has been completed and HBEL confirmed, these data should be used via a Quality Risk Management process to assess if current organisational and technical control measures are adequate, or in the case of new equipment/facility to determine what control measures are required. It is expected that the higher the hazard of products/active substances, the higher the inherent risk and the more significant organisational and technical control measures will be required. Health based exposure limits provide an accepted safe level of cross contamination and they should be used to justify cleaning limits.
How can inspectors determine the competency of the Toxicology expert developing the health-based exposure limit?
Inspectors should evaluate the company’s assessment of the competence of their expert in the field by reviewing justification of experience and qualification.
Where products for paediatric populations are manufactured in shared facilities with products intended for administration to adults or to animals, do the HBELs need adjustment?
In such facilities the standard body weight value for adults of 50 kg used for calculating the HBEL should be replaced by a lower body weight value (e.g., children: 10 kg, new-borns: 3.5 kg, prematurely born new-borns: 0.5 kg) and used for HBEL determination for all relevant products in order to reflect the worst case situation.
Is the application of the Threshold of Toxicological Concern (TTC) as applied in the guideline of mutagenic products of 1.5 µg/person/day concept an acceptable default approach to establish an HBEL?
Yes, except in the case of highly sensitising active substances and products.
Could Occupational Exposure Limits (OELs) or Occupational Exposure Bands (OEBs) be used to support assessment of products to determine whether they may be highly hazardous?
Yes. Extrapolation of an OEL or OEB (lower end of the range) to a preliminary Permitted Daily Exposure (PDE) can be simply done by using the following formula: PDE (µg/day) = OEL (µg/m3) x 10 m3 (the volume air breathed by a worker in 8 hours). Additional adjustment factors may be needed due to potential differences in target population (worker vs patient), route of exposure etc. If the resulting PDE value is 10 µg/day or lower the product should be considered as highly hazardous.
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. (WHO 2002)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function.
An adverse reaction, the nature or severity of which is not consistent with the applicable product information.
- requires inpatient hospitalization or prolongation of existing hospitalization
- Disability or Permanent Damage
- Congenital Anomaly/Birth Defect
- Important Medical Event (IME): when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes
An adverse event requires the evaluation of the presence of the following criteria by the sponsor:
- Is it a serious event?
- Is there reason to suspect a causal relationship with the administration of the investigational medicinal product?
- Is the adverse reaction, by its nature and severity, inconsistent with the reference information for the investigational medicinal product?
If the investigator or the sponsor judges all these criteria to be fulfilled, this constitutes a case of a suspected unexpected serious adverse reaction (SUSAR).
Medicinal products with a quality defect are not of the correct quality as defined by their marketing authorisation. It is important to report these defects in a timely manner because sometimes it is necessary to implement urgent measures to protect public health and animal health, such as the recall of one or more defective batch(es) of a medicine from the market or prohibition of supply.
Individual Case Safety Report (ICSR) captures information needed to support reporting of adverse events, product problems and consumer complaints associated with the use of FDA regulated products.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) developed MedDRA, a rich and highly specific standardised medical terminology to facilitate sharing of regulatory information internationally for medical products used by humans.
A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program that the U.S. Food and Drug Administration (FDA) can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.
GVP are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU). GVP apply to marketing-authorisation holders, the European Medicines Agency (EMA) and medicines regulatory authorities in EU Member States.
Guideline on GVP is divided into various chapters that are covered under modules that cover major pharmacovigilance processes and product-or population-specific considerations.
PSUR is a pharmacovigilance document intended to provide an evaluation of the risk-benefit balance of a medicinal product and should be prepared at defined time points after its authorisation.
PBRER is intended to be a common standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions. The main objective of a PBRER is to present a comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile.
As per CIOMS VIII (2010), Signal is defined as the “Information that arises from one or multiple sources which suggests a potentially new causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verification action”.
The aim of a risk management plan (RMP) is to document the risk management system considered necessary to identify, characterise and minimise the important risks of a medicinal product.
DSUR is a comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed. A DSUR provides information to assure regulators that sponsors are adequately monitoring and evaluating the evolving safety profile of the investigational drug.