1. Purpose
The purpose of this Guideline is to describe the process in place to ensure that drug products and drug substances are manufactured in a manner that minimizes patient risk through adulteration from products manufactured in the same manufacturing plant or facility.
2. Scope and Applicability
This Guideline applies to the manufacture of commercial or development products in Operations facilities.
It also applies to the manufacture of commercial or NPI (New Product Introduction) products at contractors.
It is applicable to all Operations and Research and Development sites involved in these activities.
The manufacture of development compounds in R&D facilities is out of scope.
3. Definitions
3.1 Limit of Detection (LOD)
The LOD is the lowest amount of a given substance in a sample that can be detected but not quantified with the selected analysis procedure.
3.2 Limit of Quantification (LOQ)
The LOQ is the lowest amount of a given substance in a sample that can be quantified with suitable accuracy and precision with the selected analysis procedure.
3.3 Cleaning Validation
Establishing documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
3.4 Acceptable Carryover Quantity (ACQ)
The ACQ is the potential maximum allowable quantity of previous product, which may be carried over to any subsequent product during manufacture.
3.5 Therapeutic Dose
The therapeutic dose is the amount of active substance given to a patient to achieve the desired pharmacological effect.
Note: The therapeutic dose is expressed as a weight of active substance (usually mg or g) per day.
3.6 Nil Effect Dose (NED)
Based on human data, is the maximum (single or repeated) dose at which there are no observable pharmacological effects in man.
Note: The NED is expressed as a weight of active substance (usually mg or g) per day.
3.7 Minimal Effect Dose (MED)
The minimum dose at which there is an observable pharmacological effect in man.
Note: The MED is expressed as a weight of active substance (usually mg or g) per day.
3.8 Minimum Therapeutic Dose (MTD)
The minimum amount of active substance typically given to a patient on each occasion as referenced in the Core Data Sheet.
Note: The MTD differs to the MED when the lowest observable pharmacological effect is not the desired therapeutic effect.
3.9 Maximum Daily Dose (Max DD)
The maximum dose of active substance typically administered to a patient in any 24 hr period (eg as referenced in the Core Data Sheet).
3.10 Safety Factor
The Safety Factor is the safety margin used when defining an acceptance limit for product carryover. It is applied during calculation to ensure that the level of product carryover is sufficiently low that there will not be a pharmacological effect due to any product carried over into the subsequent product.
3.11 Occupational Exposure Limit (OEL)
An in-house Occupational Exposure Limit (OEL) is a health-based exposure limit. This is the concentration of an airborne substance, averaged over a reference period, at which, according to current knowledge, there is no evidence that it is likely to be injurious to employees if they are exposed by inhalation, day after day.
4. Responsibilities
4.1 Operations Sites
Operations Sites are responsible for requesting the evaluation of relevant product changeovers by Drug Safety Review Committee (a committee within the company engaged in drug safety studies).
Note: Routine product changeovers need not be referred to committee. Referrals are usually made for unusual circumstances or changeovers involving highly potent product(s). Committee advice is non-binding to the site but deviations from committee recommendations must be justified in writing.
4.2 Drug Safety Review Committee
Is responsible for coordinating the evaluation of requests and based upon available information, providing recommendations and advice on sitting decisions to the requests. Committee shall try to provide timely advice according to the nature of the request and the production schedule.
The committee secretary is responsible for providing therapeutic dose information requested by sites/functions.
4.3 Other Functions and Departments
Other Functions and Departments (e.g. R&D and Supply Chain) are responsible for coordinating requests for any New Chemical Entities (NCEs) proposed for manufacture in Operations facilities and the application of committee recommendations.
5. Guideline
5.1 Introduction
A company which has a portfolio of products with a wide range of pharmacological potency, its manufacturing strategy usually involves the frequent use of multi-product facilities (both in-house and at contractors).
Therefore, in reviewing sitting and accommodation options for one product the impact of that product’s pharmacological potency must be considered when evaluating the potential impact of carryover of that product to other products manufactured in the same facility.
To assist Operations and R&D Functions with unusual or potent product accommodations (including accommodations at contractors) decisions, the Drug Safety Review Committee should exists to ensure that products (drug substance and drug product) are manufactured in a manner that minimizes patient risk through cross-contamination from products manufactured in the same equipment, manufacturing plant or facility. Committee is therefore a support mechanism for sites/functions to assist with difficult cleaning and product accommodation issues.
The committee comprises representatives from Supply Chain, Drug Safety, Compliance Management and members from Operations, R&D as appropriate.
For atypical product accommodations, usually involving highly potent products, Operations Sites and R&D Functions should refer to the committee for advice or endorsement of sitting decisions or product changeover proposals. Committee also provides a focal point for handling other contamination or general cleaning issues, or questions concerning company policy and procedure for cleaning.
5.2 Operating Principles for Drug Safety Committee
The head of the committee has the responsibility to set the meeting schedule as suits business needs. Although the primary purpose is commercial product manufacture, advice will be given, on request, with regard to the manufacture and sitting of development compounds, especially where these impact on Operations facilities.
The committee secretary should maintain a database of medical information for use in cleaning calculations. The committee secretary shall make such medical information available to Operations Sites and R&D functions on request. Where requests are made for product information not currently available, the committee secretary shall obtain the relevant information with the assistance of other committee members. Documented statements, signed by appropriate company medical experts, supporting the medical information shall be available from committee to support Regulatory Inspection process.
Committee should employ the same medical information used to determine the OEL, where this available, to ensure consistency between Occupational Safety and GMP approaches to patient and operator safety.
Requests for advice should be made in writing including as much information as Possible. Requests should be made to the secretary of the committee and should identify the specific issue or information required. Any relevant information on proposed manufacturing process or sitting should be included where available, as should any relevant clinical, pre-clinical safety or toxicity data where available.
Committee should maintain copy records of any recommendations provided.
Signed copies of written advice shall be provided to the requesting site or function, who are responsible for maintenance of the original signed record.
After evaluation, the output from the committee may include: recommendations on the sitting of compounds, recommendations concerning safety factors applicable for ACQ calculation, a quantitative ACQ value to which cleaning validation should be performed, additional testing or validation requirements, and/or a recommendation regarding equipment or plant dedication, where necessary.
On completion of the evaluation, committee secretary shall issue a written evaluation statement to the person requesting the information.