Audit – 21 Auditing an Excipient Supplier

Goals

When you have completed this unit, you should be able to:

a. Perform an audit of an excipient vendor

b. Use a range of tools and information, including the contents of this unit and the Internet, in support of auditing an excipient vendor

c. Understand and apply applicable GMP standards and site standards to an audit of an excipient vendor

d. Recognize compliance or non-compliance of excipient vendors to applicable regulations

Definitions

Excipient: Any material that is used in the manufacture of a Formulated Product that excludes the active ingredient; an excipient may be used during processing but not be present in the final formulation, e.g. Water.

International Pharmaceutical Excipients Council (IPEC): an international industry association formed in 1991 by manufacturers and end-users of excipients.

The association includes the United States (IPEC-Americas), Europe (IPEC Europe) and Japan (JPEC). For information, see www.ipec.org.

Pharmaceutical Quality Group (PQG): Pharmaceutical quality and GMP group that publishes codes of practice, standards, and monographs on various aspects of regulatory requirements.  For information, see www.pqg.org.

Pyrogen free:  free of fever producing substances.

Reprocessing: taking the same material and repeating steps that are already part of the normal process.

Reworking: taking already manufactured material and performing steps that are not part of the normal process.

Regrading of lot: lots manufactured for a pharmaceutical application but used as another grade, usually lower (less pure), due to failure to conform to pharmaceutical specifications.

Certification of Analysis / Certificate of Conformance: : A document issued for a batch of product or ingredient, which certifies that the batch complies with a specified quality specification.

Explanation of Topic

What is an excipient?

An excipient is an additive material used to formulate Active Pharmaceutical Ingredients (API’s) into pharmaceutical dosage forms suitable for administration to patients. Excipients are part of the final formulation of a drug product; therefore their quality and stability are important and excipient suppliers need to adhere to relevant GMPs.

Excipients are used to aid the safety, effectiveness or delivery of the dosage form.  This may include assisting in the processing of the drug delivery system; or, enhancing stability, bioavailability, or patient acceptability.

Example of common excipients:

Excipient Manufacturing

Many excipient materials are also used in industries other than the pharmaceutical industry, including food, cosmetic or industrial products.  In many cases excipients are foodstuffs, food additives, or food preservatives that are also used in pharmaceutical products.  Most pharmaceutical excipient manufacture is less than 10 percent of the production of the material.  In most cases, the material is produced in bulk and is a low margin product.

Excipient manufacturing processes are often similar to those for chemical APIs. Excipients are often manufactured on a large scale utilizing continuous processing and automated process controls.  Facilities may consist of large tanks; production facilities and equipment will vary depending upon the type of excipient being manufactured, the scale of production and the type of operations (batch processing vs continuous processing). In some cases the manufacturing plant and processes used to produce excipients may be the same as those used to produce food, cosmetic or industrial products with additional controls applied only at the isolation, packing, quality control testing and/or warehousing.

Why audit an excipient manufacturer?

Most excipients are used as purchased from the manufacturer.  Most GMP sites depend on the manufacturer to provide product that is uniform in chemical and physical characteristics and that meets established site specifications. Even though GMP site can establish specifications for the excipient, only the manufacturer can completely control the physical characteristics, the quality and the presence of impurities.

The objective of an excipient GMP audit is ensuring that the manufacture results in the uniform characteristics and quality, and the desired specifications.

To certify/qualify (in-house site certification) deliveries, the manufacturing and testing facilities used by the manufacturer need to be audited in order to evaluate possibilities for accepting material based on CoAs rather than performing full in-house testing.

GMPs for Excipient Suppliers

While there is no single regulatory document with the term “excipient” in its name, and there are no regulatory requirements that excipients be manufactured to GMPs other than for those excipient categories specified in EU legislation, there are voluntary industry standards that give guidance for applying appropriate GMP principles to excipients. These guidances include those documents used by the International Organization for Standardization (ISO), World Health Organization (WHO), and the International Pharmaceutical Excipient Council (IPEC).

While there is no single regulatory document with the term “excipient” in its name, excipients are expected to comply with the appropriate sections of GMPs as well as several other international standards for manufacturing of excipients. The standards include those documents used by the International Organization for Standardization (ISO), World Health Organization (WHO), and the International Pharmaceutical Excipient Council (IPEC).

Recently published in 2006, “The Joint IPEC-PQG Good Manufacturing Practices Guide” is the result of a collaboration between the International Pharmaceutical Excipients Council (IPEC) and the Pharmaceutical Quality Group (PQG).  The Guide  provides a baseline standard of GMPs for the manufacture of excipients. It incorporates the IPEC Good

Manufacturing Practices Guide for Bulk Excipients, 2001, with the PQG’s PS 2100:2002 Pharmaceutical Excipients and is aligned with ISO 9001.

The application of GMP is relevant once it is known that the chemical is intended for pharmaceutical manufacture. Process knowledge and risk assessment are required to determine where in the manufacturing process to begin implementing GMPs.

The excipient manufacturer is responsible for determining and documenting the rationale for the appropriate step in the process for GMP to begin being applied.  From that point on, appropriate GMP should be applied. As the manufacturing process progresses from early manufacturing to purification and packaging the stringency of GMP application should increase.

Physical processing such as granulation, milling and blending should be conducted to GMP standards.

The criticality of the process step should also be considered to determine the level of GMP control required.

Audits of an excipient manufacturer should take into account the intended use of the excipient and should focus on the quality-critical processing steps that are necessary to produce an excipient that meets criteria.

The manufacturer should identify and have adequate control over these quality critical steps to ensure a consistent process.  Quality-critical steps may include:

* phase changes ( e.g., dissolution, crystallization, evaporation, drying, sublimation, distillation or absorption)

* phase separation (e.g., filtration, centrifugation)

* chemical form changes (hydration, acetylation or formation of a salt)

* weighing or volumetric measurements that are required to be precise

* physical changes (milling, blending)

* final steps (purification, packaging, coating)

Consideration should be given to the appropriate controls for the quality critical steps and risks to final product for excipients produced sterile or pyrogen free, and for all excipients used in the formulation of parenteral or inhalation pharmaceutical dosage forms.

Key GMP Principles to consider during an audit

Control of impurities and contamination

Usually the customer does not perform further chemical processing or purification on excipients, and the material is used as purchased.  If an impurity is present in the excipient it will probably be present in the finished drug product.

The manufacturing environment should be evaluated.  External contamination can arise from the manufacturing environment when the product is exposed if adequate controls are not in place.  In excipient manufacture, chemical processes are often performed in closed systems that offer protection against environmental contamination. Consider the following factors:

• • Closed or open systems (evaluate charging and emptying from reactors)

  • Multi-use of reactors (are the same reactors used for different reactions or multipurpose, or dedicated reactors)

  • Form of the material (wet vs dry)

  • Criticality of the processing stage

  • Continuous vs batch processing

  • Potential for cross contamination

The potential risk in terms of raw materials, lubricants and manufacturing process in regards to Transmissible Spongiform Encephalopathies and compliance to current legislative guidance such as  ‘Committee for Proprietary Medicinal Products (CPMP) –

Note for Guidance on Minimizing Risk of Transmitting Animal Spongiform Encephalopathies via Human and Veterinary Products’ should be evaluated.

http://www.emea.eu.int/pdfs/vet/regaffair/041001en.pdf

Other considerations of potential raw material contamination impacts, e.g. Avian Flu, should be evaluated during the audit.

Change control

Since the excipient is used without further processing, GMP site requires consistent excipient quality – both chemical and physical parameters.  It is the responsibility of the excipient manufacturer to control excipient manufacturing processes to ensure consistent conformance to excipient specifications.

Changes in excipient manufacturing processes may result in changes of physical or chemical properties that only become evident in the finished dosage form.  This is important to a GMP site from a finished dosage form manufacturability as well as from the context of bioequivalence comparisons.  Changes made to the excipient should not impact the quality and performance of the finished dosage form.

Changes to test methods and specifications should also be controlled.

Traceability

Traceability of excipient batches is a key GMP requirement.  This includes raw material suppliers, manufacturing documentation, batch numbers, retest or expiry date, test data, Certificate of Analysis, and transportation and distribution records.

Testing of Excipients

It is important that each lot of excipient is tested in accordance with established methods to ensure compliance with agreed upon specifications.  Testing controls should include equipment qualification and calibration, training of personnel, change control, Out of

Specification result investigations, and retention of all raw data.

Key Parameters in Auditing an Excipient Supplier

Prior to the audit

Ø Determine which excipients the supplier manufactures or, if considering a new supplier, what potential excipients the new supplier will provide.

Ø Determine how the excipient(s) will be used and in what finished drug product.  If the excipient will be used as a direct component of a drug product, used in the preparation of a sterile drug product, or is represented by the manufacturer as being pyrogen free, this should make a difference in the audit.

Ø Review the status of the corrective actions from previous audits, if applicable.

Ø Determine if there have been any issues with excipients received since the last audit of the supplier.

Ø Collate data about the supplier from all related receiving sites and review that data for trends or issues.

Ø Contact procurement and determine if there have been any issues regarding supply of the excipient(s).

Ø Obtain a copy of site’s current specifications for the excipient(s).

Ø Obtain a copy of a recent CoA received by the site and compare with raw data at the excipient supplier.

Ø Review the Quality Agreement between the site and the supplier.

During the audit

A. Review the Quality System.

Ø Verify that there is an established and approved Quality System/Quality Policy that is endorsed by management.

Ø Verify that the Quality Unit is independent of manufacturing.

Ø Verify that the Quality Unit has the authority to approve or reject procedures, specifications, and process changes that impact the identity, quality, and purity of the excipient.

Ø Verify that a system is in place to notify the customer if subcontractors are used and how subcontractors are qualified.

Ø Verify that a communication system is in place to notify the customer of

1.) significant process, testing method, specification and facility changes prior to implementation and

2.) how this change will affect the excipient being produced. Verify that the Quality Control Unit’s authority and responsibilities are clearly defined in writing.

Ø Verify that an internal quality audit program for all areas of operation has been established to verify that SOP’s and other procedures and policies are being followed, and to determine the effectiveness of the quality systems.

Ø Verify that approved procedures exist for processing and investigating complaints, as well as reporting complaints and tracking resolutions.

B. Ensure that there is adequate documentation

Ø Verify that there are written SOP’s for all areas of operation.

Ø Verify that procedures are in place for the identification, collection, indexing, filing, storage, maintenance and disposition of controlled documents.

Ø Verify that there are procedures in place to insure retention of the records for every batch for at least one year past expiration or re-evaluation date (if one is assigned), or one year after distribution is complete (whichever is longer).

C. Ensure that there are sufficient qualified personnel and resources.  Personnel should have the appropriate combination of education, training and experience for their assigned job.

Ø Verify that there is a documented training and qualification program for each job classification.

Ø Verify that job-specific training is conducted and documented for each employee.

Ø Verify that training is conducted with sufficient frequency to assure that employees remain familiar with applicable regulations.

Ø Verify that there are clearly written job descriptions for all personnel.

Ø Verify that the training program incorporates requirements for temporary employees and consultants.

Ø Verify that personnel wear appropriate clothing and practice good sanitation habits.

D. Determine that the supplier has a controlled system for management of materials.

Ø Verify that there is a list maintained of approved sources for raw materials used in the manufacturing process.

Ø Verify that there is an adequate communication system to assure that suppliers and subcontractors notify the company of significant changes.

Ø Verify that there is a system in place to trace raw materials back to their original suppliers.

Ø Determine any risks associated with animal spongiform encephalopathies and other potential contamination considerations (e.g. Avian Flu).

Ø Verify that batch/lot numbers for finished product are unique and provide traceability of the batch throughout the manufacturing process.

Ø Verify that there are adequate written and approved instructions for raw material sampling and testing.

Ø Verify that appropriate controls are exercised to assure raw materials are approved prior to being used in production, and that access to quarantined material is restricted.

Ø Verify that rejected materials are adequately controlled and separated from approved or quarantined materials.

Ø Water Systems/Water Quality

E. Demonstrated to be suitable for the intended use.

Minimum – WHO guidelines for potable water

If higher requirements – specifications should be established (physical/chemical, total microbial counts, objectionable organisms and/or endotoxins).

If in-house treatment – validated process.

F. Ensure that both the receiving and distribution warehouses meet GMP standards.

Ø Verify that the warehouse is clean and well organized, with materials easily located.

Ø Verify that stock rotation is performed on a First-In-First-Out (FIFO) basis, or that there is sufficient justification for not using FIFO.

Ø Verify that an approved quarantine procedure exists which will prevent release and distribution of unapproved raw materials or product, or unapproved product shipped to customers.

Ø Verify that there are adequate distribution records maintained for all product shipments, which allow traceability in case of a recall.

Ø Verify that there is an effective management system (monitoring, retesting or re-evaluating) for stored raw materials to ensure that they are not used beyond their recommended use date.

Ø If raw materials for excipients are accepted on their certificate of analyses, verify that, at minimum, an identification test is performed on every batch received.

G. Ensure buildings, facilities and equipment meet GMP standards.

Ø Verify that the facilities are maintained in a good state of repair and cleanliness.

Ø Verify that there is a system for identifying major equipment, instruments and production lines.

Ø Verify that there is a SOP for qualifying new or significantly changed equipment.

Ø Verify that preventative maintenance and repairs, as well as calibration operations, are documented.

Ø Determine if the facility is a dedicated facility or multi-purpose.

Ø Determine if the processing equipment is dedicated to one product or used for multiple products.

Ø Determine if equipment is closed, and where product may be exposed to the environment.

Ø Determine if processing is continuous or batch.

Ø Verify that there is adequate space and environmental controls to insure product integrity and to prevent cross-contamination or product mix-ups.

Ø Verify that the manufacturing environments (all production areas) are appropriately controlled for the process taking place to protect the excipient against deterioration and contamination.

Ø Verify that there is an adequate program to protect components from contamination from insects, rodents, birds and other vermin.

Ø Verify that there are adequate ventilation systems where product is exposed.

H. Ensure that the air handling system is designed and controlled to prevent cross- contamination.

Ø Verify that the process water meets suitable standards; potable water standards at minimum.

Ø Verify adequate lighting is provided.

Ø Verify that in areas where excipient is open to the environment, drains are of adequate size and, where directly connected to a sewer, have an air break or other device to prevent back-siphoning.

Ø Verify adequate personal washing facilities are provided.

I. Ensure that the process is controlled.

Ø Verify that the supplier’s SOPs for cleaning and change over from one product to another have enough detail. Verify that there is adequate documentation to support the effectiveness of these procedures.

Ø Ensure that there is an adequate system for documenting cleaning.

Ø Determine if there are cleaning procedures for cleaning different excipient grades.

Ø Verify that there is evidence that the cleaning process for non-dedicated equipment is adequate to remove previously manufactured material.

Ø Verify that the product contact surfaces of all processing equipment are not reactive, additive, or absorptive and will not adversely affect the product.

Ø Determine if there are any other grades of the excipient.

Ø Determine if there are any other products manufactured at the site (industrial and/or toxic compounds). If there are either industrial or toxic compounds, ensure that there are containment measures and/or procedures in place to prevent contamination of excipient.

Ø Verify that there is a system to identify the status of all raw materials, intermediates and finished products. All containers and equipment should be clearly labeled to identify the contents and, if appropriate, the stage of manufacture.

Ø Verify that there are complete written manufacturing instructions/batch reports that specify quantity and identity of raw materials, equipment, manufacturing flow, operating parameters, in-process sampling, packaging materials, labeling, and documentation of each significant step.

Ø Verify that there is evidence to demonstrate that the manufacturing process produces finished product that meets established specifications consistently from batch to batch.

Ø Verify that critical process parameters have been defined.

Ø Verify that there is an adequate system, described in a SOP, for controlling process changes. The system should include

1.)  maintenance of a change log,

2.) involvement by the quality unit in the change procedure, and

3.) evaluation of the impact of the change on the excipient.

Ø Verify that there are procedures in place for investigating and determining the disposition of in-process materials, intermediates or finished excipients that do not meet specifications.  Non-conforming finished excipient lots should not be blended with conforming lots.  Procedures should be in place to prevent the blending of nonconforming finished excipient batches with conforming batches.

Ø Verify that if reprocessing (repeating steps that are already part of the normal process) is performed, there are complete written instructions including any additional testing/inspection that may be required.

Ø Verify that if reworking (performing steps that are not part of the normal process) is performed, it is reviewed and approved by an independent group. (e.g. the Quality Control Unit/ Process Development/Technical Operations).

Ø Determine if the process is in control.  Determine how many batches have been rejected, reworked or “regraded” (batches manufactured for a pharmaceutical application but used as another grade due to failure to conform to pharmaceutical specifications).

Ø Verify that there are written procedures which include commingling of fresh and recovered solvents, and that the quality of the commingled solvents is monitored according to an established schedule.

Ø Determine if recovered solvents are confined to re-use with the same process or can be used for other processes.

Ø Verify that if special storage conditions are necessary, based on the results of stability testing, and that these storage conditions are specified on the label.

Ø Determine how a batch is defined in a continuous process.

J. Ensure that computer systems have sufficient control.

Ø Verify that computer systems have been demonstrated and documented to consistently function as expected, if used in the manufacturing process.

Ø Verify that there are procedures to govern change control of computerized systems or programs, including training of personnel subsequent to changes.

Ø Verify that computer system changes are verified and documented and only made by authorized personnel.

Ø Verify that there are suitable back-up systems in place (i.e., duplicate tapes, microfilm, etc.)

Ø Verify that information can be easily retrieved from master tapes and back-up tapes.

K. Ensure that Packaging and Labeling operations have sufficient control.

Ø Verify that systems are in place to protect the quality and purity of the excipient.

Ø Verify that systems give assurance that the correct label is applied to all containers.

Ø Verify that the Packaging and Labeling operations are designed to prevent mix- ups.

Ø Ensure procedures are in place to ensure that the correct quantity of labels are printed and issued and the labels contain the correct information.  Excess labels should be immediately destroyed or returned to controlled storage.  All excess labels bearing lot numbers should be destroyed.

Ø Ensure Packaging and Labeling facilities are inspected immediately before use to ensure that all materials that are not required for the next packaging have been removed.  Direct printing should satisfy the intent above.

L. Ensure that there is a system in place to release finished product.

Ø Verify that there are complete written and approved instructions for testing of finished product. These documents should specify methods, equipment, operating parameters, and acceptance specifications.

Ø Verify that procedures are in place to insure that every batch is tested and approved before shipment, or to justify reduced testing.

Ø Verify that the finished product sampling plan assures that the sample is representative of the batch.

Ø Verify that a procedure exists to determine the disposition of finished product that does not meet specifications.

Ø Verify that nonconforming product is clearly identified and segregated to prevent use or distribution, and that access to this material is restricted.

Ø Ensure that investigation records include notification information and are maintained

Ø Verify that there is a procedure for assigning expiration and/or recommended re- evaluation dates, supported by sufficient stability data.

Ø Verify that there is an SOP for investigating returned goods, including proper identification, segregated storage, testing, and Quality Control involvement in the evaluation and determination of product disposition.

M. Ensure the Quality laboratory meets GMPs standards.

Ø Verify that training and qualifications are documented for all laboratory personnel.

Ø Verify that written and approved test methods and acceptance specifications are available to the analyst for all samples to be tested.

Ø Verify that there are procedures for qualification (IQ/OQ) of new and/or modified laboratory instruments and equipment.

Ø Verify that there are established practices to insure proper storage and handling of reference standards, reagents, volumetric and test solutions, with labeling to indicate their identity, date of preparation or receipt, expiration date and other appropriate information.

Ø Verify that there are procedures for the preparation and maintenance of complete and appropriate written laboratory records.

Ø Verify that there are procedures in place for a review of laboratory records by a second chemist, supervisor and/or the Quality Control Unit.

Ø Verify that there is a SOP for investigation of out-of-specification (OOS) results, atypical results, and test deviations, including specific procedures for re- measurement or retesting, and a time frame for completing investigations.

Ø Verify that the excipient stability has been evaluated and that the results used in determining appropriate storage and expiry or retest dates.

Ø Verify that each batch is tested against the appropriate standard and skip testing is not used.

Ø Verify that tests are performed in accordance with relevant pharmacopoeias as appropriate.

N. Verify that the Certificate of Analysis (COA) for the excipient includes the following:

Ø Name (compendial/trade), grade, pharmacopeial designations, and specific lot/batch number for the material

Ø Name of supplier, identity of the manufacturer, and manufacturing site

Ø All tests, results, and specifications for the material

Ø Date of manufacture

Ø Expiration date and/or recommended re-evaluation date

Ø Appropriate authorization (signature, title, date)

Ø Verify that there is a procedure to insure that all information on the final COA receives appropriate review, and that adequate controls are in place to prevent unauthorized changes to the COA.

O. Ensure that aseptic and sterile excipients have been produced under adequately controlled conditions.

Ø Verify that the process for sterilization of equipment has been adequately demonstrated and documented to be effective.

Ø Verify that the manufacturing environment and equipment are adequate to minimize microbiological contamination, which includes monitoring of the environment, and adequate gowning of personnel.

Ø Verify that sterility testing is performed for each batch, with procedures in place to investigate sterility failures.