IPEC-Americas Good Distribution Practices Audit Guide...

of 26 Copyright © 2011 The International Pharmaceutical Excipients Council

IPEC-Americas Good Distribution Practices Audit Guide For North American Distribution of Pharmaceutical Excipients


IPEC-Americas Good Distribution Practices Audit Guide for North American Distribution of Pharmaceutical Excipients

This document has been written to provide a tool for those auditing companies involved in the supply chain of pharmaceutical excipients. This Audit Guide should be used in conjunction with the IPEC Good Distribution Practices Guide for Pharmaceutical Excipients (2006). The explanatory notes in this Guide are provided to help the auditor obtain the maximum benefit in its application. This Guide replaces the IPEC-Americas GMP Audit Guideline for Distributors of Bulk Pharmaceutical Excipients (2000). Table of contents Page I. Introductory Note .............................................................................................................................. 3 II. Scope ................................................................................................................................................. 3 III. Pharmaceutical Grade Excipients ..................................................................................................... 3 IV. Acknowledgements .......................................................................................................................... 3 Table I: Matrix of Applicability ............................................................................................................. 4 1. Quality Management ......................................................................................................................... 5 2. Organization and Personnel ............................................................................................................... 6 3. Premises ............................................................................................................................................. 8 4. Warehousing and Storage ................................................................................................................ 10 5. Equipment ....................................................................................................................................... 12 6. Documentation ................................................................................................................................ 14 7. Repackaging and Re-labelling ......................................................................................................... 16 8. Complaints ....................................................................................................................................... 19 9. Recalls ............................................................................................................................................. 20 10. Returned Goods .............................................................................................................................. 21 11. Handling of Non-Conforming Materials ........................................................................................ 21 12. Dispatch and Transport ................................................................................................................... 22 13. Contract Activities .......................................................................................................................... 23 Appendix Bibliography ...................................................................................................................... 24


I. Introductory Note

The International Pharmaceutical Excipients Council (IPEC) first published a GMP Audit Guideline for Distributors of Bulk Pharmaceutical Excipients in 2000. This was designed as a tool to assist in evaluating the practices and quality systems of distributors who sell, store or repackage, (or any combination thereof) excipients. During 2001, and again in 2006, IPEC revised its GMP Guidelines for manufacturers of excipients and decided to publish a complementary document for distributors of excipients.

For the purpose of this guide “distributors” includes those parties involved in trade and distribution, (re)processors, (re)packagers, transport and warehousing companies, forwarding agents, brokers, traders, and suppliers other than the original manufacturer. It is recognized by IPEC that other audit guides are available and widely applied throughout the distribution industry. For definition of technical terms, please refer to the Glossary in the IPEC Good Distribution Practices Guide [7]. For auditing of manufacturing activities such as blending, mixing, milling, micronization or any other physical manipulation of pharmaceutical excipients, please refer to the IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients [2].

II. Scope

This audit guide is linked to the IPEC Good Distribution Practices Guide (based on the WHO Good Trade and Distribution Practices for Pharmaceutical Starting Materials), and therefore it follows the same structure.

It applies to all steps in the distribution/supply chain starting from the point at which an excipient is transferred outside the control of the original manufacturer's material management system. Some sections and/or sub-sections in this document may not apply to all involved parties. This document is meant to provide a framework for the auditor who must always decide to what level of detail and focus the audit must follow. It can also be used as an audit check-list by the distributor/supplier.

III. Pharmaceutical Grade Excipients

Parties involved in the supply chain should be aware that an excipient can only be pharmaceutical grade when it is in compliance with pharmacopoeial specification and/or appropriate regulatory requirements (if existing for the relevant excipient) and is manufactured, repackaged, and handled in accordance with excipient GMPs, (e.g. IPEC PQG GMP [2], WHO Excipient GMP [6]). Upgrading technical or industrial grade material to pharmaceutical grade quality based only on analytical results found in conformance with the requirements of a pharmacopoeial monograph is an unacceptable practice.

IV. Acknowledgements

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) prepared this document. IPEC is an international industry association with a distinguished worldwide membership of chemical, pharmaceutical and food firms that develop, manufacture, distribute, sell and use pharmaceutical excipients. IPEC was formed in 1991 to address prevalent industry concerns related to the harmonization of international excipient standards, the introduction of useful new excipients to the marketplace, and the development of good manufacturing practices for excipients. The IPEC Federation


is an umbrella organization comprised of regional pharmaceutical excipient industry associations. The objective of the IPEC Federation is to promote the safety and efficacy of finished dosage forms worldwide. IPEC-Americas greatly appreciates the many hours of hard work by member individuals devoted to

developing this Audit Guide and the generous support provided by their employers, with special

appreciation and recognition to Dr. Irwin Silverstein of IBS Consulting in Quality LLC for his research

and editing services.

Peter Baker Purdue Pharma, L.P. Maurice Biagini Avantor Performance Materials Charly Bonnie Univar USA, Inc. William Busch DowWolff Cellulosics Bill Campagna Eli Lilly & Company Dale Carter J.M. Huber Engineered Materials Harry Christians PharmaVize NV Kari Dylhoff Perrigo Company Marc Fages Amgen, Inc. Arthur Falk, Ph.D. IPEA Inc. James Fell Doe & Ingalls of NC, LLC William Fersch Purdue Pharma L.P. David Fillar Perrigo Company Robin Forte Catalent Pharma Solutions Tami Frederick Perrigo Company Louis Fundora Natural Response S.A. Juanita Garofalo Avantor Performance Materials John Giannone Cognis Corporation Sidney Goode, Pharm.D. PFAR Consulting Jennifer Goodman Avantor Performance Materials Richard Green CP Kelco Lisa Hart Amgen, Inc. Roger Heckman, Ph.D. LyondellBasell Industries Joyce Henry Dow Corning Corporation Linda Herzog Asahi Kasei America, Inc. Diana Hickey EMD Chemicals, Inc. Laura Horne Mutchler, Inc. Pharmaceutical Ingredients Nobuya Kaneko Asahi Kasei America, Inc. David Klug sanofi-aventis U.S. Colin Lafferty VWR International LLC Jeffrey Langa Univar USA, Inc. Cindy Libonati Purdue Pharma L.P. Iliana Lloret Americhem Pharmaceutical Corporation Roy Lyon Innophos Sherri Main Roquette America, Inc. John Mandy Pfizer Inc. Brian McCarter EMD Chemicals, Inc. Brian McCarthy FMC BioPolymer Philip Merrell, Ph.D. Jost Chemical Company Scott Messner Abbott Laboratories Linda Mikulan-Maxfield Baxter Healthcare Corporation R. Christian Moreton, Ph.D. FinnBrit Consulting Frank Murphy Dow Chemical Company Juan Otero Americhem Pharmaceutical Corporation Carl Perini International Specialty Products Michael Plover Lachman Consultant Services, Inc. Robert Przybylowski Brenntag Specialties, Inc.


Dennis Reiswig Dow Chemical Company Maria de Lourdes Rivera Maria de Lourdes Rivera Consulting Rachael Roehrig, Ph.D. Consumer Healthcare Products Association (CHPA) Richard Roswick Proctor & Gamble Company David Schoneker Colorcon Craig Scott JRS Pharma, LP Karen Seiberlich Amgen, Inc. Larry Sexton Lubrizol Advanced Materials, Inc. Irwin Silverstein, Ph.D. IBS Consulting in Quality, LLC Janeen Skutnik Pfizer Inc. Kristine Smith Abbott Laboratories Alexa Smith Colorcon John Stevenson Grace Davison Robert Sulouff III Ashland Aqualon Functional Ingredients Katherine Ulman Dow Corning Corporation Ann Van Meter DowWolff Cellulosics Ranga Velagaleti, Ph.D. BASF Corporation Phyllis Walsh Merck & Co., Inc. Robert Wiens Eli Lilly & Company Mark Wiggins Merck & Co., Inc. Diane Wood PD Regulatory Services, Inc. Priscilla Zawislak Ashland Aqualon Functional Ingredients


Table 1: Matrix of Applicability

Warehousing / Distribution (packed excipients)

Additional Processing Activities

Activity:

Section:

Transportation of packed excipients

Warehousing (storage of packed

excipients)

Brokers or Traders

Reselling packed excipients

Repackaging, Processing

Sampling, Testing and Re-testing

Relabelling Bulk handling, bulk storage

Transportation of bulk excipients

Applicability Symbol: α β γ δ ε η λ μ

1. Quality Management X+ X X+ X X X X X+

2. Organization and Personnel

X+ X+ X+ X X X X X

3. Premises X+ X X X X

4. Warehousing and Storage

X+ X X+ X

5. Equipment X X+ X X

6. Documentation X+ X+ X+ X X+ X X+ X+

7. Repackaging and Relabelling

X X+ X+ X+

8. Complaints X X X X X+ X X X

9. Recalls∗ X+ X X X

10. Returned goods X X X X

11. Handling of non-conforming materials

X+ X X X

12. Dispatch and Transport X+ X

13. Contract activities X X X X X X X X

X = applicable += only partly applicable

∗ In the USA the term recall has specific regulatory implications that do not directly apply to excipients; therefore the term retrieval is typically used in the USA.


GDP GUIDELINE APPLY TO NOTES

1. Quality Management 1.1 Quality Management System

• What quality management system is implemented? • Is there a Quality Policy?

All

1.2 Documentation and Records Quality Manual • What is the current version of the Quality Manual? If there is no Manual,

describe the quality system in place. All

Suppliers • What is the procedure to verify that any supplier of excipients, packaging

materials or services has the capability to consistently meet previously agreed requirements?

• What is the program to qualify or disqualify suppliers of raw materials, packaging components and services that might affect quality, and to verify that they have capability to consistently meet agreed-upon requirements?

• What verification technique, such as periodic audits by qualified auditors, is used to quality suppliers?

All

1.3 Describe the Quality Assurance principles• How are documents controlled? • What is the record retention policy? • Does the Quality Manual describe the scope of the Quality Management

System, organization structure, procedures, processes and resources, and the sequence and interaction between the procedures and departmental functions?

All

1.4 Conformance Expectations • Are materials purchased against an agreed specification? How is it

ensured that materials are only purchased from approved suppliers? • What procedure is in place to assure that the distributor and the customer

have mutually agreed upon the specifications and other requirements? If no procedure, what is the alternative process?

All

1.5 Personnel • What personnel are assigned responsibility to carry out all applicable

provisions of the GDP guide? • What controls are in place for the responsibilities of the Quality Unit that

have been delegated to other personnel?

All



• If contractors are used to carryout responsibilities, how have they been qualified for this purpose?

1.6 E-Commerce See 6.10 All

1.7 Release Procedures • Where excipient is provided only in originally sealed containers from the

manufacturer, is an inspection of the integrity of the packaging (including labelling) and seals carried out?

• Is a copy of the original manufacturer’s quality documents (such as Certificate of Analysis or Certificate of Cleaning) provided for each delivery along with any additional test results derived by the distributor?

β, δ, ε, η λ, μ

1.8 Certification to ISO or HAACP • If certified to ISO 9001 or HAACP, does the certifying organization assure

conformance to appropriate provisions of the IPEC-PQG GMP and IPEC GDP guide expectations?

All

1.9 Internal Audit • Describe the internal quality audit program that covers all areas of the

operation to verify that SOPs and other procedures and policies are being followed, and to determine effectiveness of the Quality System? What is the specified frequency of audits? Are audits scheduled on the importance and status of the activity performed?

• How are internal audits documented? • How are audit findings investigated? • How are management personnel made aware of the audit findings and

the corrective actions to be taken? • What evidence shows necessary steps are taken to correct areas of non-

compliance based on the findings and recommendations of the internal audits? Who is responsible for implementing the corrective actions?

• How are corrective actions documented? • Do follow-up audit activities include verification of the effectiveness of

corrective actions?

All

2. Organization and Personnel 2.1 General

• What evidence indicates resources are adequate to perform and supervise the operations carried out such as packaging, testing, storing

All



and releasing excipients in compliance with applicable GDP and GMP requirements?

2.2 Responsibility and Authority • How are qualifications (training, experience, and education) documented

and related to the assigned tasks? • How is training and qualifications documented for each employee? • Are levels of authorization clearly defined in job descriptions? • Are records maintained listing the name, address, and qualifications of

any contracted service provider and the type of service they provide?

All

2.3 Good Distribution Practices Training • What are the qualifications for individuals performing GDP training? • What records are kept to demonstrate that GDP training is conducted in a

timely manner for new and temporary employees as well as consultants and contractors?

• What is the frequency of continuing GDP training and what evidence shows it is sufficient to ensure that employees remain familiar with applicable GDP requirements? Are records kept of on-going training?

• How broadly is the training conducted within the site?

All

2.4 Competence, Awareness and Training • Who has overall responsibility for assuring appropriate personnel receive

training applicable to their task? • Describe the SOP for identifying what personnel require training

(dependent upon their task), their training need, and for providing the necessary training on a regular basis?

• How are job-specific training requirements clearly defined? • How is training effectiveness and employee competency assessed? • How are qualifications documented for each employee? • How does the training program ensure that personnel understand that

deviations from procedures may have an impact on the excipient?

All

2.5 Hazardous Materials • What training is provided to personnel dealing with hazardous materials

(such as toxic, flammable, or corrosive materials)? • What personal protective equipment is provided for handling hazardous

materials?

α, β, δ, ε, η, λ, μ



2.6 Personnel Hygiene • What personnel hygiene requirements and protective equipment are

specified and how is it communicated to employees? • How are personnel informed of the requirement to report any health

conditions that may have an adverse effect on the product? • Are personnel with illness or open skin lesions that may contaminate or

otherwise adversely affect the safety or quality of the product allowed to work in any operation that could cause the product to become contaminated?

• What is the policy on loose and/or unsecured jewelry or other items in operations where they can fall into the product? Are personnel observed to be in compliance?

• Where can personnel store and consume food, beverage, tobacco products or personal medication? How are these areas designated?

δ, ε, η, λ, μ

3. Premises 3.1 Buildings and Facilities

• Describe the space and environmental controls to ensure product integrity and to preclude mix-ups or cross-contamination during packaging and warehousing operations?

• Describe the space and environmental controls to ensure product integrity and to preclude mix-ups or cross-contamination during drying, milling, blending operations, etc.? Does it meet GMP expectations?

• What other materials are packaged or stored in close proximity to excipient where it is exposed to the environment? Does the facility use, package, or store highly sensitizing or toxic substances? Is there evidence that volatile substances are present in the environment? If so, identify those items and what controls are used to prevent contamination of the excipient? What evidence is there that these measures are effective?

• Are facilities maintained in a good state of repair? • Are there adequate laboratory facilities to perform required testing? • How much space is there around finished excipient locations in the

warehouse to facilitate cleaning?

β, δ, ε, η, λ

3.2 Security • What measures have been taken to prevent unauthorized access to the

β, δ, ε, η, λ



facility and unescorted access to packaging and warehouse areas? 3.3 Pest Control

• What measures are taken to protect excipient from contamination due to insects, rodents, birds, and other vermin (including domestic animals)? What evidence is there to show that it is adequate?

• How are windows, doors, or other openings to the outside adequately protected from entry by pests?

• If excipient is stored in silos, tanks, or other large containers, how are the vents adequately protected to prevent entry of birds and insects?

• If used, are rodenticides, herbicides and pesticides appropriately evaluated, used by trained personnel, and allowed for this type of operation?

• If an outside party performs pest control, how is that party’s performance and compliance monitored?

• Is the program supported by a site map and are reports issued? Who reviews the report?

• Are pest control records kept? What corrective and preventive measures have been taken?

β, δ, ε, η, λ

3.4 Supporting Facilities and Utilities • Is there adequate lighting? • Is the lighting protected from shattering in areas where the excipient may

be exposed or stored? • Where the excipient is open to the environment or stored, are drains of

adequate size? Are they equipped with an air break or other mechanism to prevent back flow?

• How has the effectiveness of air handling systems used to protect the excipient been demonstrated to provide such protection?

• Is ventilation such that where the excipient is exposed air handling does not contribute to the potential airborne contamination of the excipient?

β, δ, ε, η, λ

3.5 Sampling Area • How are samples taken from packaged excipient? • What is the sampling plan? How is the plan documented? • How is the area where sampling is conducted appropriately controlled to

protect the excipient against deterioration and contamination from the environment? How is the sampling area monitored?

δ, ε, η, λ



4. Warehousing and Storage 4.1 Receipt, Storage and Distribution of Materials

• What means, as described in procedures, are used to quarantine excipients on receipt until they have been approved?

• What is the basis for the approval of excipients upon receipt? How is the approval criteria documented?

• If excipient is accepted on certificate of analysis (COA), what form of verification of identity is performed on receipt?

• What additional controls for bulk deliveries are used to assure material purity and freedom from contamination (e.g. dedicated tankers, tamper-evident seals, certificate of cleaning and identification of prior content, testing, audit of the supplier, etc.)?

• How much space around stored materials is allocated to facilitate pest control and housekeeping?

• How is the dispensing of excipients monitored for appropriate accuracy where excipients are stored in silos, tanks or other large containers?

• If excipient is packaged in trucks or railroad cars, where is the cleaning of the trucks and cars documented? Does the record include identification of the previous product in the truck or railroad car?

• For non-dedicated trucks and railroad cars, how is it assured that there are no objectionable residues from prior materials?

• How are all trucks and railroad cars inspected before being filled with excipient and where is it documented?

β, δ, η, λ

4.2 Storage Areas • Is the warehouse clean and well organized, and excipients easily

located? • What special storage conditions are used for excipients that require

temperature and/or humidity control? • If excipients are stored outside, do the containers give acceptable

protection to the contents? Are labels indelible and appropriately affixed?

β, δ, η, λ

4.3 Receipt and Dispatch Bays • How are receipt and dispatch bays protected from precipitation? • Is the receiving area sufficient to allow incoming packages to be

cleaned?

β, δ, η, λ



4.4 Quarantine Facility • What means is used to quarantine rejected, recalled or returned

excipient?

β, δ, η, λ

4.5 Identification of Quarantine Area • How is the quarantine area identified; signs, computer designation, etc.?

β, δ, η, λ

4.6 Storage Conditions • Are the excipients stored in accordance with the manufacturer’s labelled

requirements, i.e. normal warehousing, specified temperatures? • What evidence shows the storage area is kept clean and dry?

β, δ, η, λ

4.7 Controlled Environment • How is the storage environment controlled to protect the excipient from

deterioration and contamination? How are conditions monitored? • If a special environment is required, how is it continuously monitored? • Is there evidence that excursions from specified conditions are

investigated?

β, δ, η, λ

4.8 Hazardous Excipient Storage • If the excipient presents a fire or explosion hazard, is it stored in a safe,

dedicated, and secure area as appropriate?

β, δ, η, λ

4.9 Bulk Handling and Storage Equipment-See 5.1 δ, λ 4.10 Spillage

• What evidence is there that spills are to be cleaned up promptly? Is there evidence to the contrary?

β, δ, η, λ

4.11 Waste Materials • How is waste segregated and storage containers identified? Is excipient

packaging ever used as waste receptacles? What is the frequency of disposal?

β, δ, η, λ

4.12 Inventory Rotation Policy • How is stock rotation managed (e.g. First in First out; Earliest Expiry First

Out)?

β, δ, η, λ

4.13 Sanitation and Pest Control • Where necessary, how are windows, doors, or other openings to the

outside adequately protected against entry by pests? If excipients are

β, δ, η, λ



stored in silos, tanks, or other large containers, how are the vents protected against entry of birds and insects?

• If used, how are rodenticides, herbicides and pesticides appropriately evaluated?

• If an outside party performs pest control, how is their performance and compliance monitored? Does the party use a site map and issue a report? What department report reviews the report?

• Where are pest control records kept and for how long? What corrective and preventive measures have been taken in the past 12 months?

5. Equipment 5.1 Design, Construction, Installation, Use, and Maintenance

• How is equipment commissioned prior to initial use? • Is equipment maintained in a good state of repair? How is preventive

maintenance scheduled? • If operations occur outdoors, what controls are in place to minimize risk

to excipient quality? • What material of construction is used so that equipment product-contact

surfaces are not reactive, additive, or absorptive and will not adversely affect the excipient?

• Is equipment designed and used in a manner that minimizes the potential for contamination of excipient with lubricants, coolants, metal or seal fragments, or other extraneous materials?

• If excipient exposure to, or contamination with, lubricants or coolants is possible, are these materials suitable for use in food applications? If a failure that leads to contamination occurs, do procedures require a documented investigation?

• What provisions are made for monitoring the product for metal contamination where appropriate?

• How is the equipment designed, where necessary, to minimize the possibility of contamination from operator contact?

• What system is in place for cleaning, inspecting and approving equipment for use after maintenance and repairs have been performed?

• Are there SOPs and appropriate documentation for inspection

δ, ε, λ, μ



(monitoring the condition) and maintenance of equipment and for measuring and test instruments? Do the SOPs assign responsibilities; include schedules; describe methods, and equipment, and materials to be used?

• Where are records kept of preventive maintenance, repairs, and use? 5.2 Layout, Design, and Use

• Is the equipment layout, design, and use such that it minimizes the risk of errors? How does it permit effective cleaning and maintenance?

δ, λ, μ

5.3 Piping • How is piping labelled with contents and direction of flow?

δ, ε, λ, μ

5.4 Marking • How are devices and utilities identified with markings? • Are connections and adapters for dangerous materials non-

interchangeable?

δ, ε, λ, μ

5.5 Balances and Devices • Are balances and other devices of suitable range and precision? • Do the SOPs for calibration of balances and devices assign

responsibilities; include schedules; describe methods, equipment, and materials to be used including standards traceable to national standards; define re-calibration frequency and limits for accuracy and precision; and require maintenance of records?

• If calibration operations are performed in-house, do the procedures specify proper handling and storage conditions for the traceable standards?

• What procedure specifies that balances and devices cannot be used if they are beyond the calibration due date?

• What actions does the calibration procedure describe to be taken regarding measurements using a balance or device that is subsequently found to have been beyond the due date or out of calibration limits, and does it require documentation of such actions?

• How is the current calibration status of balances and devices known to users?

• Where are records or logs maintained for calibration operations?

δ, ε, λ, μ

5.6 Operation and Maintenance δ, λ, μ



• See 5.1 5.7 Cleaning

• Do written cleaning procedures contain sufficient detail to allow operators to clean each type of equipment in a reproducible and effective manner?

• How have cleaning procedures been demonstrated to be effective? • What system is used for documenting cleaning and use of the

equipment (e.g. a cleaning and use log)?

δ, ε, λ, μ

5.8 Non-dedicated Equipment • If equipment is not dedicated, what other types of materials are

processed in the same equipment? What controls are used to prevent cross-contamination and how have they been justified (e.g. model product)?

• How is the record of use of the equipment documented? • What data shows that cleaning procedures for non-dedicated

equipment are adequate to remove the previous materials?

δ, ε, λ, μ

6. Documentation 6.1 Document Control

• What procedure describes the writing, handling and updating of SOPs?• Who are authorized to complete, approve, sign and date procedures? • What is the procedure for making changes to procedures?

α, β, δ, ε, η, λ, μ

6.2 Format • Do documents contain a title and describe their nature and purpose? • Are documents written in a clear easy to check format? • How is the revision history of documents displayed?

All

6.3 Certificate of Analysis (COA) • Does the COA comply with recognized guidance, including the name

and address of the site of manufacture? • How are the results determined for each test reported on the COA? Is

skip lot testing performed and indicated? • Are the manufacturer’s COA provided to the customer unaltered? What

γ, δ, ε, η, λ



supplemental testing data is also provided? • How is the COA and its data traced back to the original manufacturer or

testing laboratory? 6.4 Conformance to Specification

• How does the distributor verify the manufacturer’s COA and test results support conformance to the excipient specification?

• What procedure requires the customer be promptly informed if a receipt is nonconforming?

• Does a COA go with each shipment to the customer?

γ, δ, ε, η, λ

6.5 Traceability • How can the excipient be traced upstream to the original manufacturer?• How is the original manufacturer traced downstream to the next

recipient?

All

6.6 Transfer of Information • How is quality and regulatory information transferred from the

manufacturer to the customer?

All

6.7 Labels • Are labels applied by the distributor clear and unambiguous? • How are labels permanently affixed? • What material of construction makes labels indelible?

δ, η, λ

6.8 Labelling • Does the excipient label contain adequate information to identify the

contents, quantity, batch number, manufacturer, and retest date? • What storage conditions and handling precautions are on the label? • If labels are printed as needed, what system is used to verify the

accuracy of the labels? • How is the content of preprinted labels verified to confirm they contain

the correct information? • What security measures are taken to prevent unauthorized access to

label printing computer systems?

δ, η

6.9 Data Sheets β, γ, δ,



• How are relevant storage, handling, and safety data sheets made available?

ε, η, λ

6.10 Records • What system is used to track, control, and maintain all records that

relate to the requirements of the Good Distribution Practices? • What is the rationale for the record retention policy and where is it

documented? • Are the records legible, indelible, signed, and dated? How are they

stored to minimize deterioration or damage?

All

7. Repackaging and Relabeling 7.1 Manufacturing Processes

• Identify operations such as combining batches into a homogeneous batch, repackaging and /or relabeling. Are these operations conducted under GMP conditions? How is the risk of contamination minimized?

δ, η, λ

7.2 Special Attention • How are environmental conditions and repackaging procedures

designed to avoid contamination and cross-contamination during repackaging and relabeling operations?

• If filtered air is used in the repackaging area, how is it filtered? If not, has the use of unfiltered air been justified?

• What protective clothing are operators in the repackaging area required to wear?

• What procedure describes clearing the packaging area after each packaging operation, and cleaning before the next operation, especially if the area is used for packaging different materials?

• What procedure requires excess labels to either be immediately returned to controlled storage or destroyed? Are excess labels with batch numbers destroyed?

• How are labels controlled? • What SOP describes the receiving, reviewing, handling, storage,

issuance, and accountability of pre-printed labels? • What good sanitation and hygiene practices are in-place in repackaging

areas? • Where new batch numbers are assigned for repackaging, how is

δ, η, λ



traceability to the original batch number ensured? • When repackaging, is one batch number assigned to containers of

different batches? • Where is a copy of all labels removed from the packages kept, e.g., with

the batch records? Is a copy of the new label also kept? 7.3 Blending of Multiple Batches

• Are nonconforming batches blended or mixed with other lots that do conform to specifications?

• How are tailings or partial containers of excipient handled?

δ, η, λ

7.4 Homogeneity • Are different batches of the same excipient blended for homogeneity

and then tested? Is a COA issued with those test results? • How are customers informed that the new batch is a mixture of

batches? • When excipient is blended or mixed, how has the reproducibility of the

blending or mixing process to ensure homogeneity been demonstrated?• What are the blending parameters and/or homogeneity specifications

for the excipient? • What is the basis for the date of manufacture of the blend?

δ, η, λ

7.5 Certificate of Analysis • What agreement stipulates supplying COAs for excipient batches that

are blended? • How is the original manufacturer identified on the COA? Where

retesting is done, is the new COA also provided? How is the new COA traceable to the original?

δ, ε, η

7.6 Packaging Components • What documentation supports the use of the container/closure system,

demonstrating that it is as good as or better at protecting the excipient from deterioration and contamination than the original manufacturer packaging?

• Has the stability of the excipient in the new packaging been demonstrated?

δ, η

7.7 Reusable Containers • If returnable excipient containers are reused, how are they cleaned and

δ, η, λ



inspected before use? • Are previous labels removed or defaced?

7.8 Repackaging Area • What environmental control is in-place to protect the excipient during

repackaging from environmental contamination? • If temperature and/or humidity control is needed, how are the conditions

ensured?

δ, η, λ

7.9 Label Control • What procedure describes clearing the packaging area after each

packaging operation, and cleaning before the next operation, especially if the area is used for packaging different materials?

• What procedure requires excess labels to either be immediately returned to controlled storage or destroyed? Are excess labels with batch numbers destroyed?

• How are labels controlled? • What SOP describes the receiving, reviewing, handling, storage,

issuance, and accountability of pre-printed labels?

δ, η

7.10 Repackaged/Relabeled • How is the pharmaceutical customer informed of the original

manufacturing site by name and address?

δ, η

7.11 Identity and Quality • How is the identity and quality of the excipient ensured? • What documents provide traceability both upstream and downstream?

δ, η, λ

7.12 Batch Release • What testing is performed on repackaged excipient to assure the

quality has been maintained? • For those tests, are there complete written and approved instructions

that specify methods, equipment, operating parameters, and acceptance specifications?

• How does the Quality Unit perform batch release? Does it include review of appropriate packaging, labeling, and testing records before repackaged batches are released for sale?

δ, ε, η, λ

7.13 Test Methods • What evidence is there that the test methods used are fit for purpose?

δ, ε, λ



• If the excipient is claimed to be compliant to compendial requirements, are the test methods those defined in the appropriate pharmacopoeia? If not how have the test methods been shown to provide results that correlate to the compendial method?

• What system is in place for reviewing and implementing compendial changes?

• Does the COA reference the test method used and indicate which laboratory performed the tests?

• Where a test has not been performed on the lot, how is this indicated on the COA?

7.14 Retained Samples • Are retained samples kept for every batch for at least 1 year beyond

the retest date? • Is the retained sample size at least twice the amount required to

perform all specification testing?

δ, ε, λ

7.15 Stability Studies • What document describes the stability program? Does it specify

sample size, storage conditions, testing intervals, and tests to be performed? Is the document approved by the Quality Unit?

• Does the container used in stability testing simulate the market container?

• Is the recommended retest interval of the repackaged excipient longer than the original manufacturer’s retest interval? If so, what data supports the extended retest interval?

• If special storage conditions are needed, are they stated on the labeling?

δ, η, λ

8. Complaints 8.1 Documentation

• What procedure describes the handling of complaints? Does the procedure include actions to be taken and the criteria on which recall decisions should be based?

• Who has responsibility for investigation of complaints?

All

8.2 Investigation • How is the investigation conducted? Are investigations conducted in a

All



timely manner? • Are justified complaints investigated to their root cause? • Are follow-up actions identified? • Is the customer informed of investigatory findings? • How are complaint records periodically reviewed for trends, frequency,

and criticality in order to identify preventive actions? 8.3 Breadth of Investigation

• Where complaints are justified, has consideration been given to other affected lots? How is this documented?

All

8.4 Follow-up Actions • Where a complaint is justified, has follow-up action been considered?

α, β, γ, δ, η, λ, μ

8.5 Communication • Where a complaint is justified, how was the excipient manufacturer as

well as the customer notified?

α, β, γ, δ, η, λ, μ

9. Recalls 9.1 Procedure

• What SOP describes conducting a product retrieval or market withdrawal?

• Does the procedure describe: o How the process is managed depending upon the risk? o The decision making process with defined responsibilities? o The functions involved in the process? o The communication process and documentation? o The steps needed to retrieve the excipient?

γ, δ, η, λ

9.2 Communication to Manufacturer • Does the procedure require notification to the excipient manufacturer?

γ, δ, η, λ

9.3 Test Recall • How and when was the recall procedure last verified?

γ, δ, η, λ

9.4 Quarantine • How is recalled excipient controlled to prevent its inadvertent release

while pending investigation and disposition?

δ, η, λ



9.5 Recall Action • Are all customers and regulatory authorities notified of the decision to

recall the excipient in all countries that have received the excipient?

γ, δ, η, λ

9.6 Coordination • How are pertinent records made available to the person responsible for

the recall? • Do the records contain sufficient information to facilitate the recall?

γ, δ, η, λ

9.7 Evaluation • With what frequency is the effectiveness of the recall procedure

evaluated?

γ, δ, η, λ

10. Returned Goods 10.1 Identification, Storage, and Disposition

• What procedure describes handling returned goods, including proper identification, segregated storage, testing, and Quality Unit involvement in the evaluation and determination of its fate?

• Where are records of returned goods maintained and do those records include the appropriate information?

β, δ, η, λ

11. Handling of Non-conforming Materials 11.1 Procedure

• What procedure describes handling non-conforming excipient? • What records are maintained of nonconforming excipient related

investigations and corrective actions? • How is nonconforming excipient clearly identified and segregated to

prevent unintentional usage or sale? • If excipient is to be destroyed, is it tracked, controlled, and destroyed in

a timely and appropriate fashion? Are records of such destruction maintained?

β, δ, η, λ

11.2 Investigation • Is an investigation performed to determine if other batches are similarly

affected? Are corrective measures taken where necessary?

β, δ, η, λ

11.3 Disposition • What procedure is used for determining the fate of excipient that fails to

β, δ, η, λ



meet specifications (e.g. reprocessing, downgrading to a lesser grade, release with agreement of the customer, destruction)?

11.4 Blending • Is nonconforming excipient blended or mixed with other lots that do

conform to specifications?

β, δ, η, λ

12. Dispatch and Transport 12.1 Controlled Conditions

• How is transport selected when temperature and/or humidity control is required?

• How are these conditions monitored in transit?

α, μ

12.2 Labelling of Shipment and Storage Conditions • Do the documents that accompany a delivery list any special

requirements for transportation and storage? • Does the labelling include the original manufacturer’s name and

address?

α, μ

12.3 Communication to Carrier • How are the requirements for special transportation conditions

communicated to the carrier? • How is the ability of the carrier to meet these special conditions

assessed?

α, μ

12.4 Bulk Shipments • How are the requirements for bulk vehicles and equipment

communicated to the carrier? • How is the cleanliness of the vehicle assessed for bulk shipments?

µ

12.5 Contamination Prevention • Is dedicated equipment used for bulk shipments? If not, what

precautions are taken to prevent contamination and cross-contamination of the excipient?

α, μ

12.6 Damage Prevention • How have the packaging materials and transportation containers been

demonstrated to be suitable to protect the excipient in-transit?

α, μ

12.7 Cleaning of Bulk Equipment µ



• How have cleaning procedures been demonstrated to adequately remove the prior contents?

• Who maintains the list of restricted prior cargo in the vehicle? 12.8 Security

• How are shipments secured to prevent unauthorized access to the excipient in-transit?

α, μ

12.9 International Requirements • For shipment overseas, are international requirements in conformance

with safety aspects (e.g. explosion hazard and contamination of the environment)?

α, μ

13. Contract Activities 13.1 Contract Services

• Are contracts or technical agreements in place for all activities provided by contractors?

All

13.2 Compliance by Contract Providers • How has conformance to GDP or GMP requirements by contract service

providers been assured?

All

13.3 Contract Provider Compliance with GDP • Are contract providers in conformance with GDP? • Do operations at contract providers present a risk of contamination to

the excipient?

All

13.4 Quality Agreement • What agreement with the contract provider defines their responsibility for

conformance to GDP?

All

13.5 Subcontracting • Has the contract provider received approval from the contract giver for

any activities subcontracted especially those involving sampling, analysis, repackaging, and relabeling?

All


Appendix Bibliography

[1] Good Trade and Distribution Practices for Pharmaceutical Starting Materials World Health Organization, WHO Technical Report Series, No. 917, 2003

[2] The Joint IPEC – PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients (2006) The International Pharmaceutical Excipients Council and Pharmaceutical Quality Group,

[3] Guide to Good Storage Practices for Pharmaceuticals World Health Organization, WHO Technical Report Series, No. 908, 2003

[4] Good Manufacturing Practice for Active Pharmaceutical Ingredients (ICH Q7)

International Conference on Harmonization, 2000 [5] Model Certificate of Analysis World Health Organization, WHO Technical Report Series, No. 902, 2002 [6] Good Manufacturing Practices: Supplementary Guidelines for the Manufacture of

Pharmaceutical Excipients World Health Organization, WHO Technical Report Series, No. 885, 1999 [7] The IPEC Good Distribution Practice Guide for Pharmaceutical Excipients (2006)

The International Pharmaceutical Excipients Council, [8] The IPEC Good Manufacturing Practices Audit Guideline for Distributors of Bulk

Pharmaceutical Excipients (Now superseded by this document). The International Pharmaceutical Excipients Council, 2000

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