Tracking Number 363i1r1NSF/ANSI 363 – 20xx
© 20xx NSF InternationalIssue 1, Draft 1 (August 2011)
Not for publication. This draft text is for circulation for approval by the Joint Committee and has not been published or otherwise officially promulgated. All rights reserved. This document may be reproduced for informational purposes only.
NSF Draft Standard for
Pharmaceutical Excipients –
Good Manufacturing Practices (GMP) for Pharmaceutical Excipients
1 General
1.1Introduction
The principles outlined in this Standard provide a comprehensive basis for the quality management system used in the manufacture of pharmaceutical excipients. Implementation of these principles shall result in the achievement of three main objectives:
a)achieve excipient realization – the organization shall implement and maintain a system that delivers excipients with the quality attributes necessary to meet the requirements and expectations of customers, pharmaceutical users, and regulatory authorities,
b)establish and maintain a state of control – the organization shall ensure the manufacture and supply of excipients is in accordance with this Standard, thus providing customers with some assurance of continued suitability and reliability of supply, and
c)facilitate continual improvement – the organization shall collect objective evidence to continually develop and enhance the application of these quality management system principles to further assure excipient consistency.
1.2 Scope
This Standard is intended to define Good Manufacturing Practices (GMP) for excipient manufacture and distribution[1] for use in drug products. It sets minimum requirements for GMP applicable to all commercially available excipients.
This Standard includes the critical elements of a quality management system for excipient manufacture drawing on principles of GMP and quality systems from other relevant standards such as those referenced in section 2.2,
NOTE – The requirements of this Standard may not be sufficient for all applications of excipients. It is the user’s responsibility to determine whether or not this Standard meets the requirements for their intended use.
NOTE– Auditing excipient manufacturers ensures conformance to this Standard. This Standard is also intended to be used by duly accredited or otherwise suitably qualified 3rd parties.
NOTE– Each user of a 3rd party auditing service should make its own determination as to the qualifications of the 3rd party and the applicability of the report and/or certificate issued in satisfying its requirements, including those pertaining to its intended use of the excipient. [HJ1]
1.3 Purpose
Excipients impact the appearance, stability, and delivery of drug products and are essential to the safety, quality, and efficacy of these products. Testing of excipients cannot ensure detection of the myriad of possible contaminants and functional deficiencies from poor excipient manufacturing practices that may result in a finished drug product that is ineffective or adversely affects patient health.
2 Reference documents
2.1 Normative references
WHO, Guidelines for Drinking-Water Quality, 4th edition, 2011[2]
2.2 Informational references
The following documents were used in the creation of this Standard and provide detailed technical information:
a)European Commission, EUGuide to Good Manufacturing Practice (GMP): Annex 18 Good Manufacturing Practice for Active Pharmaceutical Ingredients, July 2001[3]
b)FDA, Guidance for Industry, Q10 Pharmaceutical Quality System, April 2009[4]
c)ICH Harmonised Tripartite Guideline, Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, November 1999[5]
d)ICH Harmonised Tripartite Guideline, Q8: Pharmaceutical Development, November 20054
e)ICH Harmonised Tripartite Guideline, Q9: Quality Risk Management, November 20054
f)ISO 9001:2008, Quality management systems – Requirements, October 2008[6]
International Pharmaceutical Excipients Council, IPEC Americas® Certificate of Analysis Guide for Bulk [HJ2][HJ3]Pharmaceutical Excipients, 2000[7]
g)International Pharmaceutical Excipients Council, IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, 20067
h)International Pharmaceutical Excipients Council, Joint IPEC – PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 20067
i)The IPEC-Americas® Significant Change Guide for Bulk Pharmaceutical Excipients, Second Revision, March 20097
j)The United States Pharmacopeial Convention, United States Pharmacopeia-NationalFormulary (USP-NF), 2011[8]
k)US FDA, Federal Food, Drug, and Cosmetic Act (FD&C Act), Section 501(a)(2)(B)[9]
3Definitions[DMPQ4][HJ5]
Terms used in this Standard, which have a specific technical meaning, are defined here.
3.1active pharmaceutical ingredient (API): Any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure, or any function of the body of man or animals.
3.2adequate: Sufficient, although not necessarily the most or the best.
3.3appropriate: A quality of being suitable for assuring conformance to the requirements.[HJ6]
3.4archival system: System used to preserve information considered valuable, using media suitable for storage and retrieval.
3.5batch: A specific quantity of material produced in a process or a series of processes so that it may be expected to be uniform in character and quality, within specified limits. In the case of a continuous process, a batch may correspond to a defined fraction of the production. The batch size may be defined by a fixed quantity or by the amount produced in a fixed time interval.[HJ7]
3.6calibration: The demonstration that a particular instrument or measuring device produces results within specified limits by comparison with results produced by using a reference or traceable standard, over an appropriate range of measurements.
3.7certificate of analysis (COA): A document listing the test methods, specifications, and results of testing a representative sample from the batch to be delivered.
3.8certificate of conformity (COC): A document that confirms the product shipped to the customer complies with a specific set of requirements or specifications. It does not contain actual test results.
3.9change control: A process used for management review of proposed changes that may impact the quality or regulatory conformance of the excipient.
3.10competency: The demonstrated personal attributes and ability to apply knowledge and skills.
3.11component: Any material present in the excipient that arises as a consequence of the raw materials and/or manufacturing process.
3.12computer system: A group of hardware components and associated software designed and assembled to perform a specific function or group of functions.
3.13contaminant: An undesired material of a chemical or microbiological nature, or foreign matter introduced from a raw material, intermediate, or excipient during production, sampling, packaging, storage or transport.
3.14contamination: The undesired introduction of impurities of a chemical or microbiological nature, or foreign matter into or onto a raw material, intermediate or excipient during production, sampling, packaging or repackaging, storage, or transport.
3.15continual improvement: Recurring activity to increase the ability to fulfill requirements.
3.16continuous process: A process that continually produces material from a continuing supply of raw material.
3.17corrective action: The action taken to eliminate the cause of a detected non-conformity or other undesirable situation. NOTE – Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence.
3.18critical: A process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the excipient meets its specifications.
3.19customer: The organization receiving the excipient once it has left the control of the excipient manufacturer; includes brokers, agents and users.
3.20documented procedure: A written procedure meeting the requirements of 4.2.3.
3.21drug product: Dosage form intended for use by a patient.
3.22effectiveness: An expression of the degree to which activities have produced the effects planned.
3.23excipient: Substances other than the API that have been appropriately evaluated for safety and are intentionally included in a drug delivery system.
3.24excipient realization: Achievement of an excipient with the quality attributes appropriate to meet the needs of internal customers, pharmaceutical users, regulatory authorities, health care professionals, and patients.
3.25expiry (expiration) date: The date designating the time before which the excipient is expected to remain within specifications and after which it must not be used.
3.26functionality: A desirable property of an excipient that aids and/or improves the manufacture, quality, or performance of the drug product.
3.27good manufacturing practices (GMP): Requirements for the quality system under which drug products and their ingredients are manufactured. Current Good Manufacturing Practices (cGMP) is the applicable term in the United States. For the purposes of this Standard, the terms GMP and cGMP are equivalent.
3.28ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
3.29IPEC: International Pharmaceutical Excipients Council.
3.30IPEC-PQG: International Pharmaceutical Excipients Council and the Pharmaceutical Quality Group.
3.31impurity: An undesirable substance component[HJ8] of an excipient that is expected to be controlled at a specified level not intended to be present in an excipient but arises as a consequence of theproduction manufacturing[O9] process or excipient degradation.
3.32justified: A documented explanation.
3.33lot: A batch or a specific identified portion of a batch. (see “batch”)
3.34mother liquor: The residual liquid that remains after crystallization or isolation processes.
3.35nonconformance:A non-fulfillment of a requirement.
3.36packaging material: A material intended to protect an intermediate or excipient during storage and transport.
3.37preventive action: The action taken to eliminate the cause of a potential non-conformity or other undesirable potential situation. NOTE –Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent recurrence.
3.38primary reference standard: A substance that has been shown by an extensive set of analytical tests to be authentic material that is of high purity and to which all like standards are traced and qualified or certified.. This standard may be:is generally (1) obtained from an officially recognized source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.
3.39process: The combination of operating steps including synthesis, isolation, purification, packaging, etc. that produces the finished excipient.
3.40product lifecycle: All phases in the life of the product from the initial development through marketing until the product’s discontinuation.
3.41production: Operations involved in the preparation of an excipient from receipt of materials operations through processing and packaging to the finished excipient.
3.42quality: The suitability of an excipient for its intended use as indicated by . This term includes relevant physical, chemical and microbiological propertiessuch attributes as the identity, strength, and purity that assure identity, purity and performance of the excipient.
3.43quality control (QC): Checking or testing that specifications are met.
3.44quality-critical: A material, process step or process condition, test requirement, or any other relevant parameter [DMPQ10]that can directly influences the quality attributes of the excipient and that must be controlled within predetermined criteria.
3.45quality management system (QMS): A management system that directs and controls how thean organization implements quality policies and achieves with regard to quality objectives.
3.46quality risk management: A systematic process for the assessment, control, communication, and review of risks to the quality of the excipient across its lifecycle.
3.47quality system: The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met.See definition of the quality management system.
3.48quality unit: An organizational unit independent of the production unit that fulfills both Quality Assurance (QA) and Quality Control (QC)responsibilities. This may be in the form of separate QA and QC units, a single individual, or a single group, depending upon the size and structure of the organization.
3.49quarantine: The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.
3.50raw material: A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or excipients.
3.51record: A document stating results achieved and/or providing evidence of activities performed. The medium may be paper, magnetic, electronic or optical, photographic, etc. or a combination thereof.
3.52representative sample: Sample comprised of a number of units taken according to a presecribed rationale obtained according to a sampling procedure so as to accurately portray designed to ensure that the different parts of a batch or the different properties of a non-uniform material are proportionately representedthe material being sampled (e.g., a batch).
3.523.53reprocessing: Repetition of an activity that is a normal part of the manufacturing process and that has been documented previously.
3.533.54requirements: The explicit or implicit needs or expectations of the governing standards.
3.543.55retained sample: A representative sample of a batch/delivery that is of sufficient quantity to perform at least two full quality control analyses and will be kept for a defined period of time.
3.553.56retest date: The date when a material must be re-examined to ensure that it is still suitable for use.
3.563.57retest/re-evaluation interval:The duration, normally expressed in months or years, from the date of manufacture, throughout which the excipient is expected to continue to conform to the specifications and after which must be tested to confirm it continues to meet the specifications.
3.573.58retest interval: (see “retest/re-evaluation interval”)
3.583.59reworking: Subjecting previously processed material that did not conform to standards or specifications to processing steps that differ from the normal process.
3.593.60risk analysis: The estimation of the risk(s) associated with the identified hazard(s).
3.603.61risk assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.
3.613.62secondary reference standard:A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.
3.623.63shelf life: The length of time during which the excipient meets specifications (see 3.25 expiry (expiration) date; 3.57 retest/re-evaluation internal; 3.58 retest interval).
3.633.64significant change: Any change that alters an excipient’s physical,or chemical or microbiological property from the norm, or that is likely to alter the excipient’s performance in the dosage form.
3.643.65solvent: An inorganic or organic liquid used as a vehicle for the presentation of solutions or suspensions in the manufacture of an excipient.
3.653.66specification: A test or list of tests, references to analytical procedures and appropriate acceptance criteria that are numerical limits, ranges or other criteria that a material is required to meet.
3.663.67specificity: The ability to assess unequivocally the analyte in the presence of components that may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
3.673.68stability: The continued conformance of the excipient to its specifications.
3.683.69state of control: A condition in which the set of controls consistently provides assurance of continued process performance and product quality.
3.693.70subcontractor: A third party for outsourced work or services that contribute in whole or in part to the manufacture of excipients.
3.703.71top management: A person or group of people who direct and control an organization at the highest level. The highest level may either be at the site or corporate level and will depend on how the quality management system is organized.
3.713.72traceability: The ability to determine the history, application, or location that is under consideration (for example, origin of materials and parts, processing history, or distribution of the product after delivery).
3.723.73validation: A documented program that provides a high degree of assurance that a specific product, method, procedure (e.g., cleaning), or system will consistently produce a result meeting predetermined acceptance criteria.
3.733.74verification: The application of methods, procedures, tests, and other evaluations, in addition to monitoring, to determine compliance with GMP principles.
4Quality Management System
4.1General Requirements
The organization shall document, manage, and implement the quality management processes and GMP required to assure excipient quality.
NOTE –The elements of the quality management processes should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognizing the different goals and knowledge available at each stage.
The organization shall maintain and continually improve the quality management system and GMP in accordance with the requirements of this Standard.
4.1.1General Quality Management Process Organization
In defining the quality management processes the organization shall:
a)define individual and collective roles, responsibilities, authorities and inter-relationships of all organizational units related to the excipient quality management system; ensure these interactions are communicated and understood at all relevant levels of the organization[i11] (see 5.5.1)[WJ12],
NOTE –An independent quality unit with authority to fulfill certain excipient quality system responsibilities is required by regional regulations.[WJ13]
b)define the interactions of the processes stated herein, with the operations needed for the quality management system and the implementation of GMP,
c)determine the criteria and methods to ensure that the operation and control of these processes and GMP are effective,
d)ensure that there are suitable resources, including availability of information, to support the operation and measurement of these processes,
e)monitor, and, where applicable, measure and analyze these processes and procedures to gain knowledge and understanding of them, and
NOTE –Processes here include the quality management system and the manufacturing and delivery operations.
f)apply actions based on the science and knowledge gained to improve these processes and the quality management system while maintaining consistent excipient quality.
NOTE– Quality risk management may be useful for identifying and prioritizing areas for continual improvement.
4.1.2Outsourcing General Requirements
Where manufacturing, testing, or other operations that may affect excipient quality are outsourced, the organization shall:
a)define the responsibility for quality and the control measures within the quality management system (see 7.4), and
b)demonstrate that the applicable GMP principles in accordance with this Standard are applied to those operations.
4.2Documentation Requirements
4.2.1General
The design, organization, and documentation of the quality system shall be structured to facilitate common understanding and consistent application.
The use of appropriate quality risk management principles shall be incorporated into changes to the quality management system.
NOTE–Quality risk management may be a useful aid to identifying activities, operations, and processes that pose a risk to consistent physical, chemical and microbiological excipient quality.