In pharmaceutical manufacturing plants there is always the doubt related to when it is necessary to have a dedicated facility or when it is possible to manufacture in a same area different products specially when some of them are steroids, sexual hormones, corticoids, cytostatics, high potency, prostaglandins, …
This lack of definition is understood in different ways for pharmaceutical companies, regulatory agencies, consultants which makes major uncertainty when making the decision about whether it is needed a dedicated facility or not for certain products.
This uncertainty has a tremendous impact on the investments to be made by a pharmaceutical company as well as in the commercial opportunities developing and manufacturing certain products.
The specific points of the most relevant regulations (EMA, FDA, ICH, WHO and PICs) with regard to compatible products in the manufacturing lines, and to the need to either have or not have dedicated facilities are gathered in the following list
Eudralex Volume 4 GMP Chapters 3.6 y 5.18
EMA /INS /GMP /809387 /2009 Update on revision of Chapter 3 and 5 of the GMP guide “Dedicated facilities”
21 CFR 211.42(d): Separation of facility and equipment
21 CFR 211.46(d): Separate air handling systems (HVAC)
21 CFR 211.176: Test for traces of penicillin where possible exposure
cGMP Guidance for industry non-penicillin beta-lactam drugs
Guidance Manual Program 7356.002 for Drug Manufacturing Inspections
ICH Good manufacturing practice guide for active pharmaceutical ingredients Q7
Annex 3 WHO Good Manufacturing Practices for Pharmaceutical Products Containing Hazardous Substances
Annex 2 WHO Good Manufacturing Practices for Active Pharmaceutical Ingredients
PICS GMP GUIDE (Part I: Basic Requirements for Medicinal Products) PE 009-10 (PartI)
3. LACK OF DEFINITION
- Mixing the GMP concepts directed to protect patients from potential cross contamination with the safety concepts directed to protect operators from the potential exposure
- There are different classifications and criteria (Safebridge, Merck, ISPE, INSHT, …) used to define the potency of a medicine. It is necessary to bear in mind that the GMPs neither define what a high potency product is nor they even refer to any guideline.
- It does not indicate what a dedicated facility is. Many people understand it as a segregated facility which implies an entire dedicated building. But everything indicates that a dedicated facility is directed to the manufacture of a certain typology of product and it can be located in the same building in which other pharmaceutical processes are carried out, providing that there is no risk of cross contamination and providing that there are correct segregation of personal and material flows and HVAC systems; the degree of segregation and protective measures should be defined by the risk analysis
- Simplistic definitions like sexual hormones or cytostatics or steroid, or enclosed terms like some hormones or some steroids …., they are vague definitions that lead to subjective and simplistic conclusions. Decisions must be made in a scientific way product by product, taking into account the tools of risk analysis described in the ICH Q9.
- The lack of definition about exceptional cases, along with campaign manufacture principle, leaves the door open for any company with correct cleaning validation criteria manufacturing these products in a multiproduct facility could be questioned with a negative feedback by any inspector, customer or consultant
To try to clarify the topic the EMA published the following document: EMA/INS/GMP/809387/2009 Update on review of Chapters 3 and 5 of the GMP Guide: “Dedicated facilities ” in this document the inspectors’ workgroup GMP/GDP of the EMA reminded
- That facilities dedicated in needed for betalactamics antibiotics and when there are manipulated pathogenic alive organisms.
- For the rest of products, the manufacturers when they introduce a new product must evaluate the product and the process to evaluate if it is possible to make of an installation multiproduct. This evaluation must be based on toxicological information of the product. When it is known that the product has a potential risk or is highly powerful or toxic, the authorities supervisors have to be asked.
There are three main targets
- Cleaning validation limits definition
- To check if there is the possibility of manufacturing a product in a multiproduct facility
- To define the risk of cross contamination with the ARL (Acceptable Residual Limit)
Regulations and guidelines to define toxicological data are:
- ICH Quality Management Q9
- ISPE Volumne-7 Risk-based Manufactured of Pharmaceutical Product
- PDA Technical report 29
- EMA/CHMP/SWP/598303/2011 Concept Paper on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities
- EMA/CHMP/ CVMP/ SWP/169430/2012 Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities
6. CLEANING LIMITS
The toxicological expert is critical to define the toxicological data that must be used to calculate the cleaning limits
The toxicological expert must define the NOAEL (No observable adverse effect level) and ADE (acceptable daily exposure), these values are critical to define the ARL (acceptable residue level)
From the ARL other variables are calculated, as the MAC (remaining admissible Maximum) or SAL (Surface limit) that allows calculating the limits of cleanliness (swabs or rinse)
For the calculation some process parameters are used as batch size, shared surfaces of contact that can diminish the cleaning limits
Process values (batch size and shared equipment surfaces among products) are used for the calculation of these variables; that allow to consider different scenarios so the bigger are the batches and smaller the contact surfaces the bigger are the cleaning limits (for example by means of dedicated or disposable equipment
Once cleaning limits have been obtained they must be cross checked against the quantification limits of the analytic cleaning methods and the real values obtained during the cleaning procedures.
The best scenario is that in which the quantification limits and the real cleaning values were lower than the obtained pre-established limit.
If quantification limits or cleaning limits are greater than the pre-established limits it could be possible to make a new calculation with larger batches size or with smaller contact surface in order to increase the theoretical limit. If after those calculations any of the criteria still don’t meet the limits, dedicated facilities would be required.
- FDA and EU required dedicated facilities for betalactamics antibiotics and when manipulating pathogenic alive organisms.
- For the rest of products the segregation and dedicated facilities should be required when the physical and procedural controls cannot demonstrate the capacity to keep under acceptable control limits the risk of cross contamination
- Objective criterion to define the risk of cross contamination by means of the ARL (acceptable residue level).
- Calculation of ARL and cleanliness limits are based on the toxicological information of the involved products, this toxicological information must be supported scientifically by a toxicological expert and if possible also by a doctor skilled in medicinal products evaluation.
- The cleanliness information along with the corresponding risk analysis is the rational one for the introduction of new products to the manufacturing areas.
INGELYT has already performed successfully these types of reports which have been supervised and approved by the different regulated agencies