“In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (eg. penicillins) or biological preparations (eg. from live microorganisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities…”
The wording requires interpretation by both industry and regulatory bodies on which certain additional products are required to be in dedicated and self-contained facilities. In the most conservative approach many companies, and regulators, have defaulted to all of these compounds should be in dedicated facilities.
This update has been long expected. The concept paper by the EMA on the need to update the GMP sections relative to cross contamination was published in February 2005. Over the past nine years, significant progress has been made to get to these updated GMP requirements. Some highlights from the documents and those events, which have influenced the final wording of the updates are as follows.
EFPIA published comments to the EMA’s concept paper in February 2005 and a “Resource Document Assessing Facilities Needs for the Manufacture of Certain Medicinal Products Using a Risk Based Approach” in November 2005. In this document, EFPIA states:
“In summary, Industry recommends that the new guidance should not define specific products or specific conditions, but should define possible criteria that may be taken into account when making a decision on manufacturing options. The final decision on conditions to be applied should then be based on a documented risk assessment of a combination of factors such as the type of product and its medical and safety risks, the type of facilities and controls applied and also the stage of production, or type of production operation being performed.”
This document set the stage for using risk assessments and risk-based approaches to determine the need for dedicated facilities.
ICH finalized Q9 Quality Risk Management in November 2005. This ICH document provides a harmonized approach to risk management in the pharmaceutical industry. FDA, EMA and MHLW all have adopted ICH Q9.
ISPE and the FDA agreed to work together on a document now known as ISPE’s Risk-MaPP Baseline in January 2006. During an ISPE Containment Conference in 2004, Edwin Melendez then of the FDA presented the FDA’s current thinking on the handling of “potent” compounds and that they would possible need to be manufactured in dedicated facilities similar to the penicillin model. Industry representatives in attendance did not feel this direction was necessary and such a stance could potentially harm the industry and possibly cause drug shortages or unavailability if dedicated facilities were required. At the 2005 ISPE Containment Conference, several industry members presented cases for science and risk-based approaches in deciding the need for dedicated facilities. At the conclusion of this session a small industry group was invited to the FDA to present this approach. A group of eight industry professionals presented science and risk-based approaches to determining the need for dedicated facilities and managing the risk of cross contamination on January 25, 2006 where the FDA at the end of the presentation agreed to work with industry through ISPE on a guideline for industry on this topic.
EMA representative of the Dedicated Facilities Workgroup becomes involved with the ISPE Risk-MaPP team in 2006. At ISPE’s 2006 Annual Meeting FDA, EMA, and PMDA participated in a panel discussion on the use of science and risk-based approaches for managing the risk of cross contamination. Catherine Lefebvre of ASMN (then AFSSAPS) represented the EMA Dedicated Facilities Working Group. After this session, Catherine became a part of the Risk-MaPP team as the liaison to the EMA Dedicated Facilities Working Group and presented status updates at many ISPE sessions. Vincent Gazin then Head of the Clinical Toxicology Unit, AFSSAPS voiced support for a science based risk-management method at the 2008 ISPE Washington Conference.
ISPE publishes the Risk-MaPP Baseline Guide in September 2010. After an industry review period and over 1,000 comments and questions from industry and regulatory bodies the final draft of the Risk-MaPP document was sent to the FDA for their final review. After incorporating the FDA comments where most notably the term ADE for acceptable daily exposure was conceived as the ADI (acceptable daily intake) term was strongly tied to the food industry and the FDA felt the ADI implied only the oral route of administration. Risk-MaPP launch sessions were given in Brussels, Washington DC, Tokyo and Singapore with regulatory participation by FDA and EMA.
EMA published draft “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities” and the EU published draft revisions to Chapters 3 and 5 for industry comment in December 2012.
The draft Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities suggests the use of the PDE, permitted daily exposure, as the health based exposure limit and provides guidance on how to determine the PDE for pharmaceutical compounds. The PDE was introduced in ICH Q3C IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS to set residual limits for solvents. The important difference in setting limits for solvents versus setting limits for pharmaceutical products is the extensive testing including with humans that pharmaceutical products must have in order to obtain approval to market the product. Solvents are not tested on humans. The guideline document seemed to imply the use of the factors as stated in ICH Q3C which could negate some of the data and information available on the compound from the various clinical trials. In addition the guidance for clinical trial materials, veterinary products and biologics was lacking sufficient detail to address the unique qualities of these types of products.
Up to the publication of these draft documents there was only speculation on how the EMA would address the updates based on presentations they made at conferences and from a few press releases published between 2005 and 2012. In addition some companies were beginning to implement science and risk-based approaches within this time. So there was great interest and many comments on these documents by industry.
The EMA hosted a workshop to discuss industry’s response to the draft GMP revisions and “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities” in September 2013. During this workshop the EMA addressed the majority of the industry comments and provided clarification on the draft guideline on setting health based exposure limits. The most notable aspect of this workshop is that EFPIA seemed to reverse their original stance of recommending that the new guidance not define specific product or specific conditions, but should define possible criteria that may be taken into account when making a decision on manufacturing options in favor of list of specific products that should follow the guidance. For more information on the outcome of this workshop see High Potency Regulations —Uncertainty remains in the quest to define certain products, Contract Pharma November/December 2013 and High Potency Regulations Re-rebuttal—Let’s move forward, allowing good science to guide the way, Contract Pharma March 2014.
So has anything changed in the final documents from the draft versions?
In short yes there are differences between the draft and the final versions of Chapters 3 and 5; some subtle and some not so subtle. Most notable is that the Guideline for setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities is not referenced in the final wording. This seems to imply that companies have some flexibility in the manner in which they perform the toxicological evaluation and set relevant residue limits. The EMA does expect to issue a final guideline for setting health based exposure limits but it appears by the removal of the reference in the final GMP wording that the guideline will not strictly be a GMP requirement but an alternative for industry to consider. This seems to be an industry preference according to the summary of comments on the draft guidance.
Other changes in the final versions from the drafts include more emphasis on the use of a QRM (quality risk management) approach and no discussion on the use of threshold values as well as other minor changes in the wording in response to the industry comments.
How should companies prepare and comply with the updates?
Companies should review their existing Quality System to determine if the company policies, standards and procedures allow the use of science and risk-based approaches to determining the need for dedicated facilities. Many companies still have policies and/or standards that require dedicated facilities for certain types of compounds regardless of the risk. These policies/standards were drafted with the original 3.6 of the EU GMPs in mind. Unless those documents are updated to allow for science and risk-based approaches dedicated facilities are required for products that fit in the internal guidelines. Other policies, standards and procedures that may require a review or update include cleaning and cleaning validation where setting acceptance limits is described. In addition it may be necessary to add policies, standards and procedures on managing the risk of cross contamination and new product introduction to the facility. The use of dedicated facilities and/or equipment remains a valid solution to manage the risk of cross contamination. However, in the absence of using only one API family in a given facility, a risk assessment is still required to show that the risk of cross contamination within the facility is being managed to an acceptable level. For example, many companies have facilities dedicated to oncology products or cytotoxic products but within these facilities several different APIs are processed. Accordingly, a toxicological evaluation which supports the APIs processed is needed to determine if these products can continue to be processed in a shared (with other oncology/cytotoxic) APIs. Chapter 3 clearly states that “dedicated facilities are required for manufacturing when a medicinal product presents a risk because:
i. the risk cannot be adequately controlled by operational and/ or technical measures,
ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitizing materials such as beta lactams) or
iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.”
Depending on the situation, the output from a defensible QRM process could result in a company attempting to further dedicate a facility within the dedicated facility (hormone, cytotoxic, oncology, etc.) to a specific API if any of the criteria above from Chapter 3 exists.
In most instances companies want to be able to use shared facilities to take advantage of cost savings and even faster time to market. To begin assessing if the product(s) can be manufactured in shared facilities, a toxicological evaluation of the APIs handled is required. If a facility has a multitude of different APIs, a plan should be developed for obtaining the toxicological evaluations - as this could take some time. Also, the regulators expect that toxicological evaluations are performed by qualified professionals and may even ask to see the credentials of the professional. Within the draft guidance on setting health-based limits from the EMA the summary worksheet did request a summary qualification of the expert.
Once the health-based limit (PDE or ADE, acceptable daily exposure, as described in ISPE’s Risk-MaPP Baseline Guide) is obtained, it can be used to determine relevant residue limits. These relevant residue limits can include acceptance limits for cleaning of shared product contact parts, non-product contact surfaces, etc. that should be used in the risk assessment portion of the QRM process.
Chapter 5—specifically 5.19, 5.20 and 5.21—provide insight into the items that should be addressed as part of the QRM process. The referenced sections clearly state the need to perform a potency and toxicological evaluation to aid assessing and controlling the risk of cross contamination. It is clear from the list of factors to be included that merely equating the hazard (PDE/ADE/health-based limit) to a given risk is not sufficient. Risk is a function of the hazard from the compound and the potential exposure to the hazard. When performing a QRM process it is important to not only look at the health-based limit of the products but also the processes and equipment used, the cleaning processes and analytical method sensitivities to determine the risks and ultimately the controls that need to be in place to manage the risks. The GMPs separate out technical measures to manage the risks from organizational controls. The reality for many will be that a matrix of both technical and organizational measures will be required.
Some notable control measures include:
- Confining manufacturing activities to a segregated, self-contained production area within a multiproduct facility. Make sure to assess the boundaries, for more information see “Are You Controlling Boundary? S. Wilkins Pharmaceutical Engineering September/October 2013.
- Using “closed systems” to minimize exposure points in processing and material/product transfer between equipment
- Using automated cleaning processes with validated effectiveness; the EMA has expressed a dislike for manual cleaning especially with high hazard compounds
- Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk
- Separating equipment washing, drying and storage areas
- Campaign processing followed by an effective validated cleaning process
- Possible verification for the cleaning of non-product contact surfaces and monitoring of air within the manufacturing area to demonstrate effectiveness of mechanical transfer and airborne contamination control measures.
- Supervising staff to ensure effective training and compliance with relevant procedural controls
The updates to the EU GMPs in regards to managing the risk of cross contamination are a major improvement to the existing uncertainty on the topic. These updates also require that the manufacturing companies truly understand the products they are handling, their facility limitations, the processes and equipment used to make quality medicines in a cost effective manner that will be safe for all patients.