Allergic reactions are not restricted to food manufacturing alone; however, there is also a rising concern about allergens in the pharmaceutical sector too. Trace amounts of allergens from different sources will cause very serious allergic responses from a small number of sensitive individuals (e.g., certain tree nuts). Therefore, increased scrutiny by FDA/EMA means that there need to be procedures established that will allow for better control of allergen contaminants and to prevent cross-contamination in the future.
A document specifying how to effectively manage allergenic-containing ingredient(s) throughout the life of the product is called an allergen control plan (ACP). This type of document will help to meet cGMP requirements as well as Quality Risk Management (QRM).
This article provides the details on important components of an ACP, what regulators expect from manufacturers regarding allergen control, how to mitigate risk of allergen contamination and how to maintain compliance with regulations while ensuring product safety.
An ACP will include:
The reason to control allergens in pharmaceuticals is that:
Common examples of allergenic substances include:
1. Eggs (albumin and ovalbumin): These are used to make vaccines and in culture media.
2. Peanuts (lecithin and soy oil): These are used as emulsifying agents and soft gel capsules.
3. Milk (lactose): This is used to help fill/dilute tablets.
4. Shellfish (chitosan): This is used to coat products and heal wounds.
5. Wheat and Gluten (starch): These are used to bind or break apart product forms.
6. Fish (gelatin): This is used in capsule shells or as a stabilizing agent.
People with sensitivities to these allergens may experience an immune response when they have residual protein from these products.
A. United States (FDA) - 21 CFR Part 211: FDA will require manufacturers to control contamination and cross-contamination (as per 211.42 & 211.67) and that they have an allergenic control as part of their contamination control strategy.
B. European Union – GMP (Annex 1 & 15): Segregation and Cleaning Validation: The EU GMP requirements state that manufacturers must separate and validate the cleaning process to prevent cross contamination of the products.
C. International Council for Harmonisation-Q9 Quality Risk Management: ICH Q9 encourages a risk based approach to identifying, assessing and controlling allergenic risks.
D. World Health Organization-GMP: Manufacturers are required to take precautions during production to prevent cross contamination of the food products by allergens or allergenic materials.
While some jurisdictions do not publish allergen guidelines for pharmaceutical products, regulators expect manufacturers to manage allergenic risks in a manner similar to their management of microbiological or chemical contamination risk.
a) Reviewing documentation and certificates of analysis (CoA) from the supplier and the supplier's supplier, to determine all of the allergens being processed in your facility.
b) Maintain an Allergen Registry of all allergenic materials used in your facility.
c) Conduct a assessment of risk for your unique situation to determine where and how you may experience cross-contact of the allergenic source - ie; during weighing, mixing, filling, packaging.
d) Consider both avenues of cross-contact - ie; direct (equipment sharing) or indirect (airborne allergenic particles, operators clothing or allergenic product containers)
The results from the risk assessment will identify the critical control points (CCP) within the facility that will outline the necessary preventive control measures for allergens.
Some best practices for the physical segregation of allergenic materials include:
The process of validation includes the following steps.
Training includes the following:
Labeling includes:
- Allergen identification and allergen processing areas.
- Records of batch manufacturing to support use of allergens.
- Warnings applied when allergen residues cannot be completely removed (if allowed by law).
- All records – from the receipt of a material through release of a batch – must be traceable for regulatory inspection.
Supplier management practices include:
- Material specifications that require allergen declarations.
- Supplier audits to verify allergen control measures.
- Inclusion of allergen clauses in quality contracts.
- Testing of high risk raw materials for allergen exposure.
Controlling your supply chain can greatly reduce your allergen risk at the source.
Monitoring includes:
- Regularly swabbing and testing surfaces for allergens.
- Inspecting visually that cleaning was performed after work with allergens.
- Trending test results to detect developing issues.
- Periodically reviewing problems and corrective actions related to allergen control.
Conducting regular internal audits of adequate allergen management practices is also recommended.
1) Change control process determines any potential allergen impact before the introduction of any new materials or processes.
2) Investigate any allergen related incidents that occur as part of the deviation management process in a timely manner.
3) Address root causes and develop preventive actions using your CAPA system.
4) Include allergen control procedures as part of the GMP internal audits.
When the integration of allergen control measures occurs, it allows systematic management and effective documentation of allergen control.
Some continuous improvement actions include:
A pharmaceutical allergen control plan is critical to the safe use of product by patients and to demonstrate compliance with regulatory requirements. In order to prevent cross-contamination of product and maintain product quality, manufacturers must use systematic processes to identify materials that are allergenic in nature, separate their operations, validate cleaning procedures and document the integrity of all processes used in their manufacturing thereof.
Allergen control is not simply an exercise in compliance; it is the embodiment of a manufacturer’s dedication to the safety of patients. When allergen management is incorporated into daily operations within a manufacturer’s facility, the manufacturer’s overall quality system is strengthened and will instill confidence in both regulatory authorities and consumers.
Ultimately, through a well-defined and pro-active allergen control strategy, a potential problem can be converted to an effectively managed process that meets both compliance and builds the confidence of patients.
This article provides the details on important components of an ACP, what regulators expect from manufacturers regarding allergen control, how to mitigate risk of allergen contamination and how to maintain compliance with regulations while ensuring product safety.
Allergen Control Plans
An allergen control plan (ACP) is a methodical process put into place to eliminate the unintentional introduction (cross-contamination) of allergenic materials into non-allergenic pharmaceutical products.An ACP will include:
- Identification of allergenic materials.
- Risk analysis of processes and equipment.
- Control mechanisms such as separation, cleaning and labeling.
- Verification and documentation systems.
Importance of Allergen Control in Pharmaceuticals
Because pharmaceuticals are generally administered to people with chronic or other health problems, exposure to allergens can have serious consequences. Even trace amounts of allergenic materials can produce hypersensitive responses in people with allergies (i.e., rash, respiratory distress; anaphylaxis).The reason to control allergens in pharmaceuticals is that:
- Patient Safety: To prevent adverse immune responses for allergic patients.
- Regulatory Compliance: The FDA and EMA expect that companies be in compliance with their GMP and Quality Risk Management (QRM) expectations in managing allergenic material risks.
- Prevention of cross-contamination from allergen to non-allergen areas of multi-product facilities.
- Prevention of product recall (costly & damaging to the brand reputation) due to allergen contamination.
Most Common Pharmaceutical Allergens
Medicinal excipients (ingredients in medications) or raw materials for medications or biological products can contain allergenic ingredients even though the vast majority of medicinal products do not have allergens from food allergy sources.Common examples of allergenic substances include:
1. Eggs (albumin and ovalbumin): These are used to make vaccines and in culture media.
2. Peanuts (lecithin and soy oil): These are used as emulsifying agents and soft gel capsules.
3. Milk (lactose): This is used to help fill/dilute tablets.
4. Shellfish (chitosan): This is used to coat products and heal wounds.
5. Wheat and Gluten (starch): These are used to bind or break apart product forms.
6. Fish (gelatin): This is used in capsule shells or as a stabilizing agent.
People with sensitivities to these allergens may experience an immune response when they have residual protein from these products.
Regulatory Requirements and Expectations
Regulators have established a requirement according to GMP regulatory authority that manufacturers must identify and control allergenic materials.A. United States (FDA) - 21 CFR Part 211: FDA will require manufacturers to control contamination and cross-contamination (as per 211.42 & 211.67) and that they have an allergenic control as part of their contamination control strategy.
B. European Union – GMP (Annex 1 & 15): Segregation and Cleaning Validation: The EU GMP requirements state that manufacturers must separate and validate the cleaning process to prevent cross contamination of the products.
C. International Council for Harmonisation-Q9 Quality Risk Management: ICH Q9 encourages a risk based approach to identifying, assessing and controlling allergenic risks.
D. World Health Organization-GMP: Manufacturers are required to take precautions during production to prevent cross contamination of the food products by allergens or allergenic materials.
While some jurisdictions do not publish allergen guidelines for pharmaceutical products, regulators expect manufacturers to manage allergenic risks in a manner similar to their management of microbiological or chemical contamination risk.
Key Elements of an Allergen Control Plan
The Allergen Control Plan should also provide continuity for the company's quality management system (QMS) and consists of the identification of potential allergens, assessments of risk associated with these allergens and their controls, verification of the effectiveness of the controls, and ongoing improvements.A. Identification and Risk Assessment of Allergens
The first step will be to identify the potential allergens within the raw materials, intermediates and finished products of your facility. Some methods to accomplish this will include:a) Reviewing documentation and certificates of analysis (CoA) from the supplier and the supplier's supplier, to determine all of the allergens being processed in your facility.
b) Maintain an Allergen Registry of all allergenic materials used in your facility.
c) Conduct a assessment of risk for your unique situation to determine where and how you may experience cross-contact of the allergenic source - ie; during weighing, mixing, filling, packaging.
d) Consider both avenues of cross-contact - ie; direct (equipment sharing) or indirect (airborne allergenic particles, operators clothing or allergenic product containers)
The results from the risk assessment will identify the critical control points (CCP) within the facility that will outline the necessary preventive control measures for allergens.
B. Material Segregation and Handling
Physically segregating allergenic materials from non-allergenic materials is one of the most effective allergen control measures.Some best practices for the physical segregation of allergenic materials include:
- Store all allergenic materials in dedicated areas that are distinctly labeled.
- Utilize different colored utensils and containers when dealing with the respective allergens/non-allergens.
- You should never have both allergen and non-allergen products being processed concurrently within the same area.
- You must have a specific or scheduled production run for each allergen/non-allergen product in order to minimize the chance of contamination of either category.
C. Cleaning and Cleaning Validation
The allergen control program includes cleaning validation as an essential component. Residual allergen material can remain on surfaces post-clean if the clean is not properly validated.The process of validation includes the following steps.
- Identify the worst case allergenic material (least soluble or stickiest).
- Create cleaning processes and agents capable of removing the identified residual materials.
- Perform analytical testing like ELISA, PCR or LC-MS to verify the absence of allergenic proteins in the sample.
- Define appropriate maximum acceptable limits of allergenics in residues based on the associated risk and toxicity data.
- Revalidate the cleaning procedure periodically and after any change in the cleaning process.
D. Personnel Training & Awareness
All employees must be aware of their responsibilities regarding the control of allergens and how they can impact on manufacturing of safe products.Training includes the following:
- Understanding how to identify the allergenic substances.
- Personal hygiene and gowning requirements.
- Cleaning and changeover procedures.
- Documenting and reporting all cross-contact incidents.
E. Labeling and Records
By labeling, companies prevent cross contamination and provide traceability to products.Labeling includes:
- Allergen identification and allergen processing areas.
- Records of batch manufacturing to support use of allergens.
- Warnings applied when allergen residues cannot be completely removed (if allowed by law).
- All records – from the receipt of a material through release of a batch – must be traceable for regulatory inspection.
F. Supplier Approval and Oversight
Suppliers have a significant role in allergen management, as most allergens come from raw materials.Supplier management practices include:
- Material specifications that require allergen declarations.
- Supplier audits to verify allergen control measures.
- Inclusion of allergen clauses in quality contracts.
- Testing of high risk raw materials for allergen exposure.
Controlling your supply chain can greatly reduce your allergen risk at the source.
G. Verifying and Monitoring
Verifying assures that you properly implement your allergen control program.Monitoring includes:
- Regularly swabbing and testing surfaces for allergens.
- Inspecting visually that cleaning was performed after work with allergens.
- Trending test results to detect developing issues.
- Periodically reviewing problems and corrective actions related to allergen control.
Conducting regular internal audits of adequate allergen management practices is also recommended.
Integrating Allergen Control into Quality Systems
An allergen management program must be a tool to complement the existing quality management program that your facility uses. The following are areas of integration:1) Change control process determines any potential allergen impact before the introduction of any new materials or processes.
2) Investigate any allergen related incidents that occur as part of the deviation management process in a timely manner.
3) Address root causes and develop preventive actions using your CAPA system.
4) Include allergen control procedures as part of the GMP internal audits.
When the integration of allergen control measures occurs, it allows systematic management and effective documentation of allergen control.
Challenges and Common Pitfalls
There are unique challenges faced when implementing an allergen control plan in an operations environment that has multiple products.- These include supplier's not providing complete allergen identification.
- There are also some facilities that rely strictly on visual inspections rather than a method of validated analytical testing.
- Another challenge is the lack of coordination between the production department and the quality assurance department.
- Inadequate cleaning validation acceptance criteria.
Ongoing Enhancement
An allergen control plan must adjust to new products, materials and regulations.Some continuous improvement actions include:
- Regular evaluation of risk assessments and validation reports.
- Tracking allergen testing results for reoccurring issues.
- Using advanced detection technologies such as LC-MS or PCR.
- Periodically updating SOPs and training programs.
A pharmaceutical allergen control plan is critical to the safe use of product by patients and to demonstrate compliance with regulatory requirements. In order to prevent cross-contamination of product and maintain product quality, manufacturers must use systematic processes to identify materials that are allergenic in nature, separate their operations, validate cleaning procedures and document the integrity of all processes used in their manufacturing thereof.
Allergen control is not simply an exercise in compliance; it is the embodiment of a manufacturer’s dedication to the safety of patients. When allergen management is incorporated into daily operations within a manufacturer’s facility, the manufacturer’s overall quality system is strengthened and will instill confidence in both regulatory authorities and consumers.
Ultimately, through a well-defined and pro-active allergen control strategy, a potential problem can be converted to an effectively managed process that meets both compliance and builds the confidence of patients.
Frequently Asked Questions (FAQs) on Allergen Control Plan for Pharmaceuticals
Q1. What is an Allergen Control Plan (ACP)?
Answer: An allergen control plan (ACP) is used to identify, control and prevent allergen cross-contamination of pharmaceutical products. The ACP should be documented to indicate that the plan has been adhered to and to provide evidence of compliance.Q2. Why is allergen control important?
Answer: Allergen control is important because it prevents allergic reactions, keeps the patients safe and meets regulatory compliance.Q3. Which materials are common allergens in pharmaceuticals?
Answer: The most common allergens found in pharmaceutical products are lactose, egg-derived ingredients, soy lecithin, gelatin and chitosan but there may be others.Q4. How are allergens controlled during manufacturing?
Answer: Allergens are controlled during manufacturing by a process of segregation, validated cleaning, labelling and risk based monitoring.Q5. How is allergen cleaning validated?
Answer: Validation of allergen cleaning is performed by analytical testing such as ELISA or PCR to detect the removal of any residual allergens.Q6. Who is responsible for allergen control?
Answer: Each manufacturing facility has its own allergen control plan and therefore the responsibility to control allergens is shared between quality team, production team and procurement team.Q7. How often should allergen control be reviewed?
Answer: An allergen control procedure should be reviewed annually or after any manufacturing process or raw material change.Q8. What happens if allergen contamination occurs?
Answer: If a cross-contamination incident occurs then the affected batch will be quarantined and a full investigation will take place and corrective actions will follow.
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